WO2012122295A2

WO2012122295A2 - Treatment for pancreatic adenocarcinoma and other cancers of epithelial origin

Info

Publication number: WO2012122295A2
Application number: PCT/US2012/028112
Authority: WO
Inventors: Rebecca LAMBERT
Original assignee: Ned Biosystems, Inc.
Priority date: 2011-03-07
Filing date: 2012-03-07
Publication date: 2012-09-13
Also published as: WO2012122295A3

Abstract

The present invention is directed to compositions and methods for the treatment of pancreatic cancer. Compositions comprising a plurality of nutraceutical and non-chemotherapeutic drug components directed to addressing cancer-supportive processes in a patient are disclosed.

Description

TREATMENT FOR PANCREATIC ADENOCARCINOMA AND OTHER CANCERS OF EPITHELIAL ORIGIN

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. Provisional Application No. 61/450,049 filed March

7, 2011, the entire contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention is directed to a treatment for cancer, in particular cancers of epithelial origin and, more particularly, pancreatic cancer. The treatment involves novel combinations of nutraceutical and non-chemotherapeutic drug products aimed at inhibition of cancer-supportive signaling or metabolic pathways and stimulation of cancer-suppressive signaling or metabolic pathways.

BACKGROUND OF THE INVENTION

Pancreatic cancer is an aggressive disease associated with an extremely poor prognosis. It is one of the most malignant cancers, characterized insidious onset, usually late diagnosis and low survival rate after diagnosis. Pancreatic cancer was the fourth leading cause of cancer death in the United States in 2010, and the 5-year survival rate is only 6% (Jemal et al., CA Cancer J. Clin., 60(5): 277-300 (2010)).

Factors associated with the risk for developing pancreatic cancer include cigarette smoking, increased body mass index (obesity), heavy alcohol consumption, and a diagnosis of diabetes mellitus (Klein, A., Mol. Carcinog., 51(1): 14-24 (2012)). Inherited genetic factors also play an important role in pancreatic cancer risk. Pancreatic cancer is a fundamentally genetic disease caused by both inherited and acquired genetic mutation. Inherited genetic variation plays an important role in both the familial and non- familial (sporadic) occurrences of pancreatic cancer. It is estimated that 5-10% of pancreatic cancer patients have a family history of pancreatic cancer (Lynch et al., Semin. Oncol, 23: 251-275 (1996); Hruban et al., Adv. Surg., 44: 293-31 1 (2010)). While the genetic mutations responsible for the majority of the clustering of pancreatic cancer in families have yet to be identified, several pancreatic cancer genes have been established, including both high-penetrance genes such as BRCA2 (Murphy et al., Cancer Res., 62: 3789-3793 (2002)); STK11 (Su et al., Am. J. Pathol, 154: 1835-1840 (1999)); pl6/CDKN2 (Lynch et al., Cancer, 94: 84-96 (2002)); and PALB2 (Jones et al., Science, 324: 217 (2009)); and low-penetrance genes such as the ABO blood group locus (Amundadottir et al., Nat. Genet., 41 : 986-990 (2009)).

Only 10-15% of patients with pancreatic cancer have disease amenable to surgical resection, and the recurrence rate is high even with radical surgery. Although some progress has been made in developing new diagnostic methods and novel targeted therapies, the overall survival rate has not improved over the last decade. The impairment of drug delivery pathways caused by the low density of vasculature within pancreatic tumors makes pancreatic tumors highly resistant to chemotherapy. Systemic treatment of pancreatic cancer thus has only modest benefits (Burris et al., J. Clin. Oncol , 15: 2403-2413 (1997); Andersson et al., Scand. J. Gastroenterol , 44: 782-786 (2009)). Patients with pancreatic cancer usually present with locally advanced, unresectable or metastatic disease and are often sensitive to the adverse effects of more intensive treatments. Therefore, postoperative chemotherapy or radiation therapy may not be viable options.

Although pancreatic cancer patients are largely resistant to radiation therapy, the reported results to date suggest that the use of induction chemotherapy can select patient populations without early metastatic disease who can benefit from consequent aggressive local therapy of

chemoradiation, which provides local control for palliation of symptoms and improved survival. However, there is insufficient evidence to recommend chemoradiation in patients with locally advanced unresectable pancreatic cancer as a superior alternative to chemotherapy alone. Recent studies using regional intra-arterial chemotherapy which was expected to increase the local drug concentration has generated promising results, and clinical trials in pancreatic cancer have been focusing on developing more effective treatment regimens by combining cytotoxic chemotherapy agents with molecular targeted therapies.

Presently, the standard of treatment remains systemic chemotherapy with gemcitabine, with palliative objectives and a disappointing marginal survival advantage. Very recently, the demonstration of a clinically and statistically meaningful survival advantage with the 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) regimen over single-agent gemcitabine

(Conroy et al., N. Engl. J. Med., 364: 1817- 1825 (201 1)), and the introduction of nanoparticles of albumin-bound paclitaxel (nad-paclitaxel) to putatively target the desmoplastic stroma characteristic of pancreatic ductal adenocarcinoma (PDAC) (Garber, K., J. Natl. Cancer Inst., 102: 448-450 (2010)), have raised hope that innovative combinations and improved delivery of classical cytotoxics may indeed substantially affect chemotherapy efficacy in advanced PDAC.

Molecular targeting of pathways that are dysregulated in pancreatic cancer is a promising approach, however targeted agents or combinations of targeted agents and conventional therapeutics have thus far failed to improve outcomes in pancreatic cancer. The reasons for such failure may include selection of largely inactive agents, failure to address simultaneously activated pathways, lack of an extensive early clinical testing, and lack of appropriate patient selection. A better understanding of pancreatic cancer biology, and an extensive preclinical and early clinical evaluation of novel molecular targeted drugs are urgently needed to improve the prognosis for pancreatic cancer patients (Milella et al., J. Clin. Oncol , 26: 4637 (2008)).

The current emphasis of conventional oncology research and practice is on the use of pharmaceutical agents that are targeted molecular therapies - mostly small molecule drugs and monoclonal antibodies that target one or more specific genetic/molecular markers, designed to suppress or block entire pathways associated with those target molecules. Many of these drugs are FDA-approved for various cancers, but only one for pancreatic cancer— ERLOTINIB (Tarceva). But the extent of ERLOTINOB's clinical utility has been widely acknowledged among gastrointestinal oncologists as being extremely limited. One possible reason for its limitation is that it is trained on a single molecular target in a malignancy which relies on a multiplicity of pathways to maintain its unrestrained growth.

Addressing multiple pathways at once holds great promise for development of new cancer treatments. The use of customized cocktails of multiple targeted agents, or discovery of single drugs with multi-targeting capabilities, is much discussed in the field but is an approach that has not been adequately explored.

Therefore, despite marginal advances in pancreatic cancer treatment, there remains a need for improved therapies and more creative approaches to devising and delivering effective pancreatic cancer therapies.

SUMMARY OF THE INVENTION

The present invention relates in general to methods and compositions for the treatment of cancer, more particularly for the treatment of epithelial cell related cancers, and more particularly for the treatment of pancreatic cancer. The improved treatment methods and regimens described herein are the product of a novel and comprehensive approach to the development of individualized treatments for cancer. The approach to treatment recognizes that cancer growth and metastasis depends on unchecked cellular processes, in particular angiogenesis, and simultaneously the activation of multiple metabolic and signaling pathways in the patient. Pathways that in a normal individual would suppress, or at least not support, cancer growth are inactive, blocked or attenuated in a cancer patient; likewise, pathways that are cancer-supportive, which are held in check or counterbalanced in a normal individual, are amplified in a cancer patient. The object of the therapeutic approach of the present invention is to inhibit or attenuate angiogenesis as well as to rebalance as many of the metabolic, intercellular signaling, and intracellular signaling pathways that are detected or suspected to be contributing to the survival or growth of the cancer. More particularly, the objects of the treatment protocol described herein are to achieve one or more of the following:

· blocking, interrupting, or attenuating tumor angiogenesis (i.e., the formation and

development of the vasculature that tumors need in order to thrive and progress) or pathways that support angiogenesis, including disruption of signaling inducing vasculogenic mimicry;

• reducing, blocking, or reversing the mechanisms of chemo-resistance to chemotherapeutic drugs, in order to enhance effectiveness of chemotherapy, preferably while increasing anti- tumor, pro-apoptotic activity;

• supporting a metabolic shift from aerobic glycolysis (the "Warburg Effect") to glucose oxidation, which promotes or renews a diminished capacity for undergoing apoptosis;

• blocking, interrupting, or attenuating intracellular tumor cell signal transduction pathways that promote tumor cell growth;

• inhibiting intercellular signaling pathways that facilitate tumor invasion into local tissues and tumor metastasis (i.e., the spread of tumor cells to other tissues or organs);

• reducing the toxic side effects of chemotherapy and any other active ingredients added to a treatment regimen; and

• augmenting or enhancing the patient's host defenses (particularly the host immune system), their general health and well-being.

In a particularly preferred embodiment, the methods and compositions are individually tailored to the patient in need of treatment and are based on a number of parameters measured in, for example, blood samples or tissue biopsies taken from the patient to be treated, to determine the optimal combination and dosages of each compound of the composition selected for the treatment of that individual. It is also contemplated that, once the cancer is in remission (e.g., by following the methods and teachings disclosed herein), the patient can continue on a treatment regimen according to the invention, in order to maintain or lengthen the period of remission, or until one or more abnormally upregulated cancer-supportive metabolic and/or signaling pathways or one or more abnormally downregulated cancer-suppressive metabolic and/or signaling pathways return to normal. In this way, following the methods of the invention helps to prevent recurrence of the disease.

The treatment of the present invention comprises administration of a combination of active ingredients, which may be administered in addition to conventional anticancer therapeutics

(chemotherapeutic agents), which combination will include naturally occurring compounds, nutrients, extracts or other nutraceutical compounds such as, for instance, Curcumin, Grape Seed Extract, Green Tea Extract ((or epigallocatechin gallate, EGCG), Boswellia, etc., and non- chemotherapeutic agents, such as, for instance, Metformin, Tetrathiomolybdate, Naltrexone, Melatonin, etc. The composition to be administered to the cancer patient may comprise a combination of from 3 to 28 or more of these nutraceutical compounds and non-chemotherapeutic drugs. The combination of compounds and dosage of each will be determined by one skilled in the art, for example, the patient's oncologist or primary care physician.

Therefore, the present invention is directed in general to a unique integrative approach to cancer therapy, in which conventional oncology is merged with complementary modalities. The complementary aspect emphasizes the use of natural compounds and non-chemotherapeutic drugs to augment conventional therapies to promote synergistic effects or compound effects, in which all the components of treatment are designed to collectively abrogate angiogenesis and the oncogenic signaling transduction pathways within cancer cells and the intercellular signaling between tumor cells and their local cellular and biochemical micro-environment, to the end that all or as many biological systems as possible that contribute to the survival of the cancer will be addressed, to the detriment of the cancer and to the improvement of health of the patient. The novel approach described herein has been demonstrated to improve the conventional treatment of pancreatic adenocarcinoma but will also be suitable for the treatment of other cancers, e.g., other cancers of epithelial origin (such as breast cancer, esophageal cancer, uterine cancer, liver cancer, etc.), and all forms of cancer or other diseases where regulation of angiogenesis and multiple signaling pathways is called for.

In its broadest aspects, therefore, the present invention provides a composition for administration to a patient diagnosed with cancer, particularly pancreatic cancer, optionally as an adjunct to a chemotherapy, a composition comprising at least three ingredients, each of which is capable of regulating a specific metabolic pathway or intracellular signaling pathway or intercellular signaling pathway implicated in the advent of the cancer, wherein at least three such pathways are addressed. The compositions of the invention may be in the form of an admixture of three or more ingredients, or they may simply be separate ingredients composed to be used together, so that specific endogenous pathways or processes in the cancer patient are treated simultaneously.

In one embodiment, a composition according to the invention comprises at least three different compounds, wherein at least one compound is selected from three of the following four tables, Tables 1-4:

Alpha Lipoic Acid Milk Thistle Extract (Silymarin)

Vitamin C Vitamin E

In an embodiment, a composition of the present invention comprises the combination of Naltrexone, Metformin, and Tetrathiomolybdate. In further embodiments, one or more nutraceutical compounds are added to this combination.

In a further embodiment, a composition of the present invention is comprised of at least five different compounds, wherein at least one compound is selected from each of the four Tables 1 -4, above.

In a further embodiment, a composition according to the invention comprises Curcumin, Genistein, Vitamin D3, N-acetyl Cysteine, and Green Tea Extract (or epigallocatechin gallate, EGCG). In a further embodiment, a composition according to the invention comprises the foregoing five compounds and, in addition, Naltrexone, Metformin, and Tetrathiomolybdate.

In another embodiment, a composition according to the invention comprises at least eight different compounds, with at least two compounds selected from each of Tables 1, 2, 3, and 4, above.

In a further embodiment, a composition according to the invention comprises Curcumin, Genistein, Vitamin D3, Tetrathiomolybdate, N-acetyl Cysteine, Green Tea Extract (or

epigallocatechin gallate, EGCG), Metformin, and Naltrexone. In a further embodiment, a composition according to the invention comprises the foregoing eight compounds and, in addition, Wobenzym® N enzyme blend.

In another embodiment, a composition according to the invention comprises at least thirteen different compounds, with at least two compounds being selected from each of Tables 1, 2, 3, and 4, above. A particular embodiment is a composition comprising Curcumin, Genistein, Vitamin D3, Tetrathiomolybdate, N-acetyl Cysteine, Green Tea Extract - EGCG, Metformin, and Naltrexone, further comprising five additional compounds selected from Tables 1, 2, 3, and 4.

In a further embodiment a composition according to the invention comprises at least eight different compounds, wherein at least one compound is selected from each of Tables 1, 2, 3, 4, 5 and

Melatonin Metformin

Naltrexone

In another embodiment, a composition according to the invention comprises at least fifteen different compounds, with at least one compound selected from each of Tables 1, 2, 3, and 4, above.

In another embodiment, a composition according to the invention comprises at least fifteen different compounds, with at least one compound selected from each of Tables 1, 2, 3, 4, 5, and 6, above.

In another embodiment, a composition according to the invention comprises at least twenty- two different compounds, with at least one compound selected from each of Tables 1, 2, 3, 4, 5, and 6, above.

In another embodiment, a composition according to the invention comprises at least twenty- seven different compounds, with at least one compound selected from each of Tables 1, 2, 3, 4, 5, and 6, above.

In another embodiment, a composition according to the invention comprises at least twenty- eight different compounds, with at least one compound selected from each of Tables 1, 2, 3, 4, 5, and 6, above.

In another embodiment, a composition according to the invention comprises at least thirty- one different compounds, with at least one compound selected from each of Tables 1, 2, 3, 4, 5, and 6, above.

In a further embodiment, a composition according to the invention comprises twenty-eight compounds selected from the compounds set forth in Table 7, or equivalents thereof:

Apigenin

Boswellia

Baicalein (Scutellaria baicalensis), Chinese Skullcap

Curcumin

Grape Seed Extract

Melatonin

N- Acetyl Cysteine

Omega 3 - Fish Oil

Pycnogenol

Quercetin

Resveratrol

Selenium

Vitamin D3

Zinc (Gluconate or Acetate)

Green Tea Extract - EGCG

Wobenzym® N

Naltrexone

Metformin

Tetrathiomolybdate

Alpha Lipoic Acid

Acetyl- 1 -carnitine

Genistein (pure)

Milk Thistle Extract (Silymarin)

Vitamin C

Vitamin E

Fucoidan

Graviola Active Pectin

Rhodiola

Rosemaria

Sulforaphane

The foregoing composition is advantageously used as a supplement to standard chemotherapeutic agents.

In a preferred embodiment, the invention provides a supplement for treatment of pancreatic cancer, comprising the compounds listed in Table 8 below, in sufficient dosages to provide the respective daily amounts:

Naltrexone 4.5 mg

Metformin 500 mg

Tetrathiomolybdate 120 mg (4 x 30 mg)

Alpha Lipoic Acid 1200 mg (4 x 300 mg)

Acetyl- 1 -carnitine 1000 mg (2x 500 mg)

Genistein (pure) 8400 mg (6 x 1400 mg)

Milk Thistle Extract (Silymarin) 500 mg

Vitamin C 2000 mg (4 x 500 mg)

Vitamin E 1200 IU (3 x 400 IU)

Fucoidan 300 mg

Gravida 3000 mg (4 x 750)

Active Pectin 1000 g (2 x 500 mg)

Rhodiola 100 mg

Rosemaria 500 mg (2 x 250 mg)

Sulforaphane 800 μg (2 x 400 μ )

For each of the compounds listed in Tables 1-8, substitutions may be made of equivalent compounds that contain the same active ingredient as the original compound or which have a similar effect on the same cellular process (such as angiogenesis), metabolic pathway, intracellular signaling pathway, or intercellular signaling pathway as the original compound. Suitable equivalents for the preferred compounds listed in Tables 1-8 are discussed infra.

The present invention also contemplates the use of any of the previously described compositions in the treatment of cancer, more particularly in the treatment of a cancer of epithelial origin, more particularly pancreatic cancer.

In further embodiments, the present invention involves the use of a composition comprising at least three compounds, wherein at least one compound is selected from three of the Tables 1, 2, 3, and 4, above, for making a medicament for treating an individual suffering from cancer, more particularly for the treatment of a cancer of epithelial origin, more particularly for the treatment of pancreatic cancer. In further embodiments, the present invention involves the use of a composition comprising at least five compounds, wherein at least one compound is selected from each of Tables 1, 2, 3, and 4, above, for making a medicament for treating an individual suffering from cancer, more particularly for the treatment of a cancer of epithelial origin, more particularly for the treatment of pancreatic cancer. In further embodiments, the present invention involves the use of a composition comprising at least eight compounds, wherein at least two compounds are selected from each of Tables 1, 2, 3, and 4, above, for making a medicament for treating an individual suffering from cancer, more particularly for the treatment of a cancer of epithelial origin, more particularly for the treatment of pancreatic cancer. In further embodiments, the present invention involves the use of a composition comprising at least thirteen compounds, wherein at least two compounds are selected from each of Tables 1, 2, 3, and 4 above, for making a medicament for treating an individual suffering from cancer, more particularly for the treatment of a cancer of epithelial origin, more particularly for the treatment of pancreatic cancer. In further embodiments, the present invention involves the use of a composition comprising at least eight compounds, wherein at least one compound is selected from each of Tables 1, 2, 3, 4, 5, and 6 above, for making a medicament for treating an individual suffering from cancer, more particularly for the treatment of a cancer of epithelial origin, more particularly for the treatment of pancreatic cancer. In further embodiments, the present invention involves the use of a composition comprising at least fifteen compounds, wherein at least one compound is selected from each of Tables 1, 2, 3, 4, 5, and 6 above, for making a medicament for treating an individual suffering from cancer, more particularly for the treatment of a cancer of epithelial origin, more particularly for the treatment of pancreatic cancer. In further embodiments, the present invention involves the use of a composition comprising at least twenty -two compounds, wherein at least one compound is selected from each of Tables 1, 2, 3, 4, 5, and 6 above, for making a medicament for treating an individual suffering from cancer, more particularly for the treatment of a cancer of epithelial origin, more particularly for the treatment of pancreatic cancer. In further embodiments, the present invention involves the use of a composition comprising at least twenty-seven compounds, wherein at least one compound is selected from each of Tables 1, 2, 3, 4, 5, and 6 above, for making a medicament for treating an individual suffering from cancer, more particularly for the treatment of a cancer of epithelial origin, more particularly for the treatment of pancreatic cancer. In further embodiments, the present invention involves the use of a composition comprising at least thirty-one compounds, wherein at least one compound is selected from each of Tables 1, 2, 3, 4, 5, and 6 above, for making a medicament for treating an individual suffering from cancer, more particularly for the treatment of a cancer of epithelial origin, more particularly for the treatment of pancreatic cancer. In further embodiments, the present invention involves the use of a composition comprising the compounds listed in Table 7, above, for making a medicament for treating an individual suffering from cancer, more particularly for the treatment of a cancer of epithelial origin, more particularly for the treatment of pancreatic cancer.

The present invention also provides a method for treating an individual suffering from pancreatic cancer comprising administering to said individual a composition comprising at least three different compounds, wherein at least one compound is selected from three of the following four tables, Tables 1-4:

In a further embodiment, the present invention provides a method for treating an individual suffering from pancreatic cancer comprising administering to said individual a composition comprising the combination of Naltrexone, Metformin, and Tetrathiomolybdate. In further embodiments, one or more nutraceutical compounds are administered along with this combination.

In a further embodiment, the present invention provides a method for treating an individual suffering from pancreatic cancer comprising administering to said individual a composition comprised of at least five different compounds, wherein at least one compound is selected from three of the four Tables 1 -4, above. In a further embodiment the present invention also provides a method for treating an individual suffering from pancreatic cancer comprising administering to said individual a composition comprising Curcumin, Genistein, Vitamin D3, N-acetyl Cysteine, and Green Tea Extract - EGCG. In a further embodiment, the method includes administering the foregoing five compounds and, in addition, Naltrexone, Metformin, and Tetrathiomolybdate.

In another embodiment, the present invention also provides a method for treating an individual suffering from pancreatic cancer comprising administering a composition comprising at least eight different compounds, with at least two compounds selected from each of Tables 1, 2, 3, and 4, above.

In a further embodiment the present invention also provides a method for treating an individual suffering from pancreatic cancer comprising administering a composition comprising Curcumin, Genistein, Vitamin D3, Tetrathiomolybdate, N-acetyl Cysteine, Green Tea Extract - EGCG, Metformin, and Naltrexone. In a further embodiment, the method includes administering the foregoing eight compounds and, in addition, Wobenzym® N enzyme blend.

In yet another embodiment, the present invention also provides a method for treating an individual suffering from pancreatic cancer comprising administering a composition comprising at least thirteen compounds, with at least two compounds being selected from each of Tables 1, 2, 3, and 4, above. In a further embodiment the present invention also provides a method for treating an individual suffering from pancreatic cancer comprising administering a composition comprising Curcumin, Genistein, Vitamin D3, Tetrathiomolybdate, N-acetyl Cysteine, Green Tea Extract - EGCG, Metformin, and Naltrexone, and further comprising five additional compounds selected from Tables 1, 2, 3, and 4.

In another embodiment, the present invention also provides a method for treating an individual suffering from pancreatic cancer comprising administering a composition comprising at least eight different compounds, wherein at least one compound is selected from each of Tables 1 , 2, 3, 4, 5 and 6:

Resveratrol Green Tea Extract - EGCG

Baicalein Genistein

Naltrexone

Sulforaphane

In another embodiment, the present invention also provides a method for treating an individual suffering from pancreatic cancer comprising administering a composition comprising at least fifteen different compounds, with at least one compound selected from each of Tables 1, 2, 3, and 4, above.

In another embodiment, the present invention provides a method for treating an individual suffering from pancreatic cancer comprising administering a composition comprising at least fifteen different compounds, with at least one compound selected from each of Tables 1, 2, 3, 4, 5, and 6, above.

In another embodiment, the present invention also provides a method for treating an individual suffering from pancreatic cancer comprising administering a composition comprising at least twenty -two different compounds, with at least one compound selected from each of Tables 1, 2, 3, 4, 5, and 6, above.

In another embodiment, the present invention provides a method for treating an individual suffering from pancreatic cancer comprising administering a composition comprising at least twenty- eight different compounds, with at least one compound selected from each of Tables 1, 2, 3, 4, 5, and 6, above.

In another embodiment, the present invention also provides a method for treating an individual suffering from pancreatic cancer comprising administering a composition comprising at least thirty-one different compounds, with at least one compound selected from each of Tables 1 , 2, 3, 4, 5, and 6, above.

In another embodiment, the present invention also provides a method for treating an individual suffering from pancreatic cancer comprising administering a composition comprising at least twenty-seven compounds, wherein at least one compound is selected from each of Tables 1, 2, 3, 4, 5, and 6, above.

In another embodiment, the present invention provides a method for treating an individual suffering from pancreatic cancer comprising administering a composition comprising twenty-eight compounds selected from the compounds set forth in Table 7, or equivalents thereof:

Apigenin

Boswellia

Baicalein (Scutellaria baicalensis), Chinese Skullcap

Curcumin

Grape Seed Extract

Melatonin

N- Acetyl Cysteine

Omega 3 - Fish Oil

Pycnogenol

Quercetin

Resveratrol

Selenium

Vitamin D3

Zinc (Gluconate or Acetate)

Green Tea Extract - EGCG

Wobenzym® N

Naltrexone

Metformin

Tetrathiomolybdate

Alpha Lipoic Acid

Acetyl- 1 -carnitine

Genistein (pure)

Milk Thistle Extract (Silymarin)

Vitamin C

Vitamin E

Fucoidan

Graviola Active Pectin

Rhodiola

Rosemaria

Sulforaphane

In the foregoing method, said composition is advantageously used as a supplement to standard chemotherapy.

In a preferred embodiment, the present invention provides a method for treating an individual suffering from pancreatic cancer comprising administering to said individual a composition comprising the compounds listed in Table 8 below, in sufficient dosages to provide the respective daily amounts:

Wobenzym® N Complex (3 times daily)

Naltrexone 4.5 mg

Metformin 500 mg

Tetrathiomolybdate 120 mg (4 x 30 mg)

Alpha Lipoic Acid 1200 mg (4 x 300 mg)

Acetyl- 1 -carnitine 1000 mg (2x 500 mg)

Genistein (pure) 8400 mg (6 x 1400 mg)

Milk Thistle Extract (Silymarin) 500 mg

Vitamin C 2000 mg (4 x 500 mg)

Vitamin E 1200 IU (3 x 400 IU)

Fucoidan 300 mg

Gravida 3000 mg (4 x 750)

Active Pectin 1000 g (2 x 500 mg)

Rhodiola 100 mg

Rosemaria 500 mg (2 x 250 mg)

Sulforaphane 800 μg (2 x 400 μ )

In the foregoing methods, substitutions may be made for the compounds listed in Tables 1-8 of equivalent compounds that contain the same active ingredient as the original compound or which have a similar effect on the same metabolic pathway, intracellular signaling pathway, or intercellular signaling pathway as the original compound. Suitable equivalents for the preferred compounds listed in Tables 1-8 are discussed infra.

In yet another embodiment, the present invention provides a method for treating an individual suffering from pancreatic cancer comprising administering any of the compositions as set forth above and wherein the patient is also undergoing chemotherapy. In a further aspect of this embodiment, the chemotherapy comprises Gemcitabine. In yet a further aspect of this embodiment, the chemotherapy comprises Gemcitabine, Docetaxel, Rigosertib, Capecitabine (GTX), and combinations thereof.

In yet another aspect of this embodiment, the chemotherapy comprises 5-fluorouracil. In another aspect of this embodiment, the chemotherapy comprises 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX). The present invention also provides a method for treating an individual suffering from pancreatic cancer comprising the steps:

(a) detecting abnormally elevated levels in pancreatic tissue or blood of said individual of one or more pro-angiogenic regulators selected from the group consisting of VEGF, MMP-9, MMP- 2, TNF-a, IGF- 1, CXCR4, TGF-β, EGFR, IL- Ι β, IL-6, bFGF, PDGF-BB, IL-8, Angiogenin, IL- l a, and Leptin, and/or detecting abnormally low levels of angiostatin or other anti-angiogenic regulator in pancreatic tissue or blood of said individual;

(b) detecting abnormal or undesirable activation of at least two metabolic, intercellular signaling, or intracellular signaling pathways identified in groups I, II, III, IV, and V, below, and wherein abnormal or undesirable activation is detected for pathways in at least two separate groups: Group I: Molecular, Genetic, and Intracellular Signaling Pathways

PI3K/AKT/mTOR

RAS/RAF/MEK/ERK (also known as MAP-Kinase (MAPK) Pathway, or ERK 1/ 2 Pathway) cross-talk between PI3K/AKT/mTOR and RAS/RAF/MEK/ERK (MAPK) pathways

Epidermal Growth Factor Receptor (EGFR)

HEDGEHOG

cross-talk between HEDGEHOG and mTOR pathways

Insulin Growth Factor- 1 (IGF- 1)

cross-talk between IGN- 1 and Focal Adhesion Kinase (FAK) pathways

VEGF

cross-talk between VEGF and EGFR pathways

BCL-2 (BCL-X_L and MCL- 1)

IAP family (inhibitors of apoptosis), including, e.g., clAP l , cIAP2, XIAP, NAIP, ML-IAP, ILP2, Livin, Apollon and Survivin

NF-kappaB (NFKB)

Mirk/Dyrk IB

vasculogenic mimicry

Group II: Tumor Suppression

p53, p21 gene disruptions or mutations

mitochondrial respiration

Group III: Metabolic Regulation

aerobic glycolysis, oxidative stress, Warburg effect, COX-2 activation Group IV: Cell Cycle Arrest

apoptosis dysregulated

Group V: Enzymatic or Endocrine Abnormalities

enzyme or endocrine levels abnormal

(c) administering a composition comprising at least one compound selected from the group of compounds corresponding to the pathway activation detected in (a) and (b) according to the following Table 9, said compound being administered in an amount effective to alter said abnormal or undesirable pathway activation toward normal, that is, toward a level of activity in an individual not exhibiting pancreatic cancer:

enzyme abnormality, deficiency Wobenzym® N

Tables 7 and 8, above, show a list of nutraceuticals and non-chemotherapeutic

pharmaceuticals that can be advantageously administered as part of the treatment regimen described herein for treating a patient diagnosed with pancreatic cancer. The list of Table 8 includes typical daily doses for each compound. It will be understood by practitioners in the field that the dosages will be tailored to the individual patient based on, for example, the results of a blood analysis of the patient, monitoring patient progress, etc., to determine which compounds from the list, and what dosages of each, will be most beneficial, i.e., provide the highest likelihood for reducing the size of the tumor. Through continual monitoring of the patient, the compounds and dosages will be adjusted accordingly.

DEFINITIONS

A method according to this invention for treating an individual with a cancer, for example a cancer of epithelial origin, in particular pancreatic cancer involves or comprises administering to the individual a therapeutically effective amount of a composition as described herein comprising a plurality of nutraceutical compounds and/or non-chemotherapeutic pharmaceuticals. Such compositions may be administered alone or, preferably, in addition to (e.g., to supplement or as a co- agent with) conventional cancer pharmaceutical. The term "therapeutically effective amount" applied to any individual component of a composition according to the invention means an amount which, when administered to the individual in need, will block, attenuate, or reverse a cancer- supportive process occurring in said individual, or will enhance or increase a cancer-suppressive process in said individual. In the context of cancer treatment, a "therapeutically effective amount" is an amount which, when administered to an individual diagnosed with a cancer, will prevent, inhibit, or reduce the further development of cancer in the individual. A particularly preferred

"therapeutically effective amount" of a composition described herein reverses (in a therapeutic treatment) the development of a malignancy such as a pancreatic carcinoma or helps achieve or prolong remission of a malignancy. A therapeutically effective amount administered to an individual to treat a cancer in that individual may be the same or different from a therapeutically effective amount administered to promote remission or inhibit metastasis.

As with most cancer therapies, the therapeutic methods described herein are not to be interpreted as, restricted to, or otherwise limited to a "cure" for cancer; rather the methods of treatment are directed to the use of the described compositions to "treat" a cancer, i.e., to effect a desirable or beneficial change in the health of an individual who has cancer. Such benefits are recognized by skilled healthcare providers in the field of oncology and include, but are not limited to, a decrease in tumor size (tumor regression), an improvement in vital functions (e.g., improved function of cancerous tissues or organs), a decrease or inhibition of further metastasis, a decrease in opportunistic infections, an increased survivability, a decrease in pain, improved motor function, improved cognitive function, improved feeling of energy (vitality, decreased malaise), improved feeling of well-being, restoration of normal appetite, restoration of healthy weight gain, and combinations thereof.

In addition, regression of a particular tumor in an individual (e.g., as the result of treatments described herein) may also be assessed by taking samples of cancer cells from the site of a tumor such as a pancreatic adenocarcinoma (e.g., over the course of treatment) and testing the cancer cells for the level of metabolic and signaling markers to monitor the status of the cancer cells to verify at the molecular level the regression of the cancer cells to a less malignant phenotype. For example, tumor regression induced by employing the methods of this invention would be indicated by finding a decrease in any of the pro-angiogenic markers discussed above, an increase in anti-angiogenic markers described herein, the normalization (i.e., alteration toward a state found in normal individuals not suffering from cancer) of metabolic pathways, intercellular signaling pathways, or intracellular signaling pathways that exhibit abnormal activity in individuals diagnosed with cancer. The term "treating" also may include the reduction, stabilization, regression, elimination of pancreatic cancer or other cancers related to abnormal growth of epithelial cells. The term "treating" may also include the promotion of cellular health in one or more organs or systems of the individual prescribed a treatment regimen as described herein.

A composition or method described herein as "comprising" one or more named elements or steps is open-ended, meaning that the named elements or steps are essential, but other elements or steps may be added within the scope of the composition or method. To avoid prolixity, it is also understood that any composition or method described as "comprising" (or which "comprises") one or more named elements or steps also describes the corresponding, more limited composition or method "consisting essentially of (or which "consists essentially of) the same named elements or steps, meaning that the composition or method includes the named essential elements or steps and may also include additional elements or steps that do not materially affect the basic and novel characteristic(s) of the composition or method. It is also understood that any composition or method described herein as "comprising" or "consisting essentially of one or more named elements or steps also describes the corresponding, more limited, and closed-ended composition or method "consisting of (or "consists of) the named elements or steps to the exclusion of any other unnamed element or step. In any composition or method disclosed herein, known or disclosed equivalents of any named essential element or step may be substituted for that element or step.

A "composition" according to this invention, or a "pharmaceutical composition", refers to the combination of two or more nutraceuticals and/or non-chemotherapeutic pharmaceuticals as described herein for co-administration or administration as part of the same regimen. It is not required that the combination of components result in physical admixture, that is, administration as separate co-agents each of the components of the composition is possible; however many patients or practitioners in the field may find it advantageous to prepare a composition that is an admixture of two or more of the ingredients in a pharmaceutically acceptable carrier, diluent, or excipient, making it possible to administer the component ingredients of the combination at the same time. As used herein, the term "pharmaceutically acceptable" applied to the carrier, diluent, or excipient used to formulate a composition as disclosed herein means that the carrier, diluent, or excipient must be compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

As used herein, the term "pharmaceutically-acceptable salt" means a salt prepared by conventional means, and are well known by those skilled in the art. Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids included but not limited to hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic, ammonium, tetaalkylammonium, and valeric acids and the like. General information on types of pharmaceutically acceptable salts and their formation is known to those skilled in the art and is as described in general texts such as "Handbook of Pharmaceutical salts" P. H. Stahl, C. G. Wermuth, 1st edition, 2002, Wiley-VCH.

DETAILED DESCRIPTION OF THE INVENTION

The ensuing detailed description provides exemplary embodiments of the invention, and the disclosure of specific examples is not intended to limit the scope, applicability, or configuration of the invention. Following the detailed description will permit and enable the skilled practitioner to put to use all the embodiments of the invention described herein and covered by the appended claims. It will be understood that various changes may be made to the specific combinations and/or arrangement of the elements or compounds without departing from the description or coverage of the claims. Substitution of known equivalents or specific equivalents disclosed herein for any named component of a pharmaceutical composition described in the application will be within the skill of practitioners in the field of this invention.

"Angiogenesis" refers to the generation of new blood vessels into a tissue or organ. Under normal physiological conditions, humans or animals only undergo angiogenesis in very specific restricted situations. For example, angiogenesis is normally observed in wound healing, fetal and embryonal development, and formation of the corpus luteum, endometrium, and placenta. The endogenous control of angiogenesis is a highly regulated system of angiogenic stimulators and inhibitors. The control of angiogenesis has been found to be altered in certain disease states and, in many cases, the pathological damage associated with the disease is related to uncontrolled angiogenesis.

Angiogenic regulators in the human or animal body can generally be divided into two main groups: (1) pro-angiogenic regulators that directly or indirectly stimulate capillary and blood vessel growth, and (2) anti-angiogenic regulators or endogenous inhibitors that retard angiogenesis.

Examples of pro-angiogenic regulators include, for example, Tumor Necrosis Factor (TNF-a), Granulocyte Colony-Stimulating Factor (GCSF), and Vascular Endothelial Growth Factor (VEGF). Examples of anti-angiogenic regulators include, for example, Interferon gamma (IFN-γ), Interleukin- 12 (IL-12), Thrombospondin- 1 , and Angiostatin.

In many diseases and in cancer in particular, angiogenesis is an important process that supports the disease, and therefore the process of angiogenesis itself becomes a target for therapeutic intervention. Recent medical research has documented the essential role angiogenesis plays in supporting disease. Angiogenesis is particularly well documented as a pivotal process in cancer, wherein avascular benign tumors are transformed into life-threatening malignant tumors.

Both controlled and uncontrolled angiogenesis are thought to proceed in a similar manner.

Endothelial cells and pericytes, surrounded by a basement membrane, form capillary blood vessels. Angiogenesis begins with the erosion of the basement membrane by enzymes released by endothelial cells and leukocytes. The endothelial cells, which line the lumen of blood vessels, then protrude through the basement membrane. Angiogenic stimulants (pro-angiogenic regulators) induce the endothelial cells to migrate through the eroded basement membrane. The migrating cells form a "sprout" off the parent blood vessel, where the endothelial cells undergo mitosis and proliferate. The endothelial sprouts merge with each other to form capillary loops, creating the new blood vessel. In the disease state, prevention of angiogenesis can avert the damage caused by the invasion of the new microvascular system.

Persistent, unregulated angiogenesis occurs in a multiplicity of disease states, including tumor metastasis and abnormal growth by endothelial cells, and angiogenesis supports the pathological damage seen in these conditions. The diverse pathological states created due to unregulated angiogenesis have been grouped together as angiogenic dependent or angiogenic associated diseases. Therapies directed at control of the angiogenic process seek to abrogate or mitigate development of these diseases. Angiogenesis has become an important target for cancer treatment with the recognition that it is one of the critical events necessary for cancer growth and metastasis. As a tumor develops, its size is limited by the diffusion of metabolites from existing blood vessels. Tumor angiogenesis is essential for cancerous tumors to keep growing and spreading.

As a tumor grows, cells at the center become starved of oxygen, inducing the expression of a transcription factor, hypoxia inducible factor- 1 (HIF- 1), which upregulates the expression of a range of angiogenic factors. Growth factor signaling also initiates HIF-1 activity, pre-empting the need for growing cells to maintain oxygen homeostasis. As a result, HIF-1 itself has been isolated as a therapeutic target for cancer.

In addition to angiogenesis, many processes or pathways in an individual become altered in an individual suffering from cancer, compared to the same processes or pathways as they function in normal individuals not suffering from cancer. The pathways affected by cancer include metabolic pathways (e.g., regulation of glucose metabolism, hormone release and uptake, etc.), intercellular signaling pathways (e.g., regulation of cell proliferation, migration, circulation as a function of the regulation of cytokines and growth factors), and intracellular signaling pathways (e.g., differential gene expression, cell cycle perturbation or arrest, mutation, etc.).

Table 10 contains a listing of pathways that have been found to be altered in patients diagnosed with pancreatic cancer. They are involved in both the intracellular signal transduction pathways that drive pancreatic tumor cell growth and the intracellular signaling pathways that promote angiogenesis, tumor invasion into normal tissues and the extracellular matrix, and tumor cell metastasis through lymphatic channels and the bloodstream to other tissues and organs. In some instances, established "cross-talk" or interaction between certain signaling pathways is deemed so extensive that it is included as an additional separate pathway.

vasculogenic mimicry

enzymatic or endocrine abnormalities

mitochondrial respiration abnormalities

apoptotic dysfunction

The foregoing list is not in order of importance, because the relative importance of certain pathways undoubtedly differs, at least to some extent, from patient to patient. Only an

individualized, or "personalized" genomic, molecular, or proteomic tumor cell analysis would be able to provide insight into which pathways are relatively more powerful in their contribution to carcinogenesis and tumor progression in any one patient. The treatment regimen developed herein is expected to integrate this personalized approach in future implementation with pancreatic cancer patients by providing regular testing of signaling proteins to monitor the impact of the therapy and provide direction in optimizing the individualized dosing.

Pancreatic cancer is a cancer of epithelial origin, and therefore it is expected that many of the same pathways will be implicated in other epithelial cancers, such as breast cancer, uterine cancer, esophogeal cancer, liver cancer, etc. The disruption of normal metabolic, intercellular signaling, and intracellular signaling pathways is a characteristic of cancer generally, although the range of pathways affected and the degree will vary with the type of cancer and from patient to patient.

Nevertheless, the principles of treatment developed herein with regard to pancreatic cancer will be advantageously practiced to augment the treatment of other epithelial origin cancers and cancer in general.

The methods and compositions described herein are designed to either interfere, block, attenuate, or, where appropriate, enhance the functioning of the endogenous pathways listed in Table 10. The combination of compounds and their dosages in a composition according to the invention will be calculated to affect a plurality of the pathways detected or suspected of being abnormally activated or suppressed in a patient. Preferably a combination of at least three pathways in addition to one or more pro-angiogenic pathways will be addressed by the ingredients of the composition. By "addressed" is meant that the process or pathway will be altered by the administration of one or more of the composition components toward normalcy, that is, toward the characteristic function of that process or pathway in a normal individual, or an individual that does not suffer from the cancer being treated. Detection of normal or abnormal functioning of the pathways listed in Table 10 is within the skill of practitioners in this field.

Nutraceuticals and Non-chemotherapeutic Pharmaceuticals for use in Compositions of the Invention Natural compounds and supplements referred to as "Nutraceuticals", "Natural Medicines", or

"Phytomedicines" that are suitable for use in preparing the compositions of the invention are discussed below. These nutraceuticals have been selected based on the quality and number of preclinical or clinical studies presenting either credible evidence of clinical anti-tumor activity in human cancer patients or demonstrating their ability to affect the tumorigenic and angiogenic signaling pathways listed above, and/or to interfere with the noted "cross-talk" between pathways that is essential for tumor cells to proliferate, for angiogenesis to flourish, and for tumor progression.

Clinical trials mostly offer access to Phase I or II studies of targeted therapies that, again, may target just one marker, or in some cases, several markers. Currently approved cancer therapies typically involve the selection of a single chemotherapeutic agent found to have a direct impact on cancer cell growth and administering as much of that agent as can be tolerated by the patient without being fatally toxic. The concept of the present invention is that addressing only one pathway with a chemotherapeutic drug leaves several other cancer-supportive pathways unchecked or cancer- suppressive pathways unenhanced, which may leave the cancer alternative pathways of angiogenesis, growth, or migration. By contrast, with natural compounds and non-chemotherapeutic drugs, although their potency against any one target is less than that of a rationally designed pharmaceutical, the combination of multiple natural compounds (nutraceuticals) and/or non-chemotherapeutic pharmaceuticals (preferably including multiple agents against individual target pathways) has the potential to address multiple pathways with multiplicative pharmacologic potencies.

Nutraceuticals typically include natural, bioactive chemical compounds or any substance that is a plant, food, an extracted part of a food, that provides medical or health benefits but which generally fall outside regulations controlling pharmaceuticals. Included in this category of substances may be foods, isolated nutrients, supplements, and herbs. Nutraceuticals are often referred to as phytochemicals or functional foods and include dietary supplements. Numerous nutraceuticals have been described (see, for example, Roberts et al., Nutraceuticals: The Complete Encyclopedia of Supplements, Herbs, Vitamins, and Healing Foods , 1^st Edition (Perigee Trade 2001); Susan G. Wynn, Emerging Therapies: Using Herbs and Nutraceuticals for Small Animals (American Animal Hospital Assn. Press 1999); and Handbook of Nutraceuticals and Functional Foods, Robert E. C. Wildman, ed. (CRC Press 2001). Examples of nutraceuticals useful in the present invention include, but are not limited to, Amino Acids, Terpenoids, Carotenoid Terpenoids (Lycopene, Beta-Carotene, Alpha-Carotene, Lutein, Zeaxanthin, Astaxanthin), Herbal Supplements, Homeopathic Supplements, Glandular Supplements, Non- Carotenoid Terpeniods (Perillyl Alcohol, Saponins, Terpeneol, Terpene Limonoids), Polyphenolics, Flavonoid Polyphenolics (Anthocyanins, Catechins, Isoflavones, Hesperetin, Naringin, Rutin, Quercetin, Silymarin, Tangeretin, Tannins), Phenolic Acids (Ellagic Acid, Chlorogenic Acid, Para-Coumaric Acid, Phytic Acid, Cinnamic Acid), Other Non-Flavonoid Polyphenolics (Curcumin, Resveratrol, Lignans), Glucosinolates,

Isothiocyanates (Phenethyl Isothiocyanate, Benzyl Isothiocyanate, Sulforaphane), Indoles (Indole-3- Carbinol (13C), Thiosulfonates, Phytosterols (Beta-Sitosterol), Anthraquinones (Senna, Barbaloin, Hypericin), Capsaicin, Piperine, Chlorophyll, Betaine, Pectin, Oxalic Acid, Acetyl-L-Carnitine, Allantoin, Androsterondiol, Androsterondione, Betaine (Trimethylglycine), Caffeine, Calcium pyvurate (Pyruvic Acid), Carnitine, Carnosine, Carotene (alpha & beta), Carotenoid (Total for beadlets), Choline, Chlorogenic Acid, Cholic Acid (Ox Bile), Chondroitin Sulfate, Chondroitin Sulfate (Total Mucopolysaccharides), Cholestin, Chrysin, Coenzyme Q 10 (Co-Q l O), Conjugated Linoleic Acid (CLA), Corosolic Acid, Creatine, Dehydroepiandrosterone (DHEA), Dichlorophen, Diindolymethane (DIM), Dimethyglycine (DMG), Dimercapto Succinic Acid (DMSA), Ebselen, Ellagic Acid, Enzymes, Fisetin, Formonetin, Glucaric Acid (Glucarate), Glucosamine (HC1 or Sulfate), Glucosamine (N- Acetyl), Glutathione (Reduced), Hesperidine, Hydroxy-3-Methylbutyric Acid (HMB), 5-Hydroxytryptophan (L-5-HTP), Indole-3-Carbinol, Inositol, Isothiocyanates, Linolenic Acid-Gamma (GLA), Lipoic Acid (alpha), Melatonin, Methylsulfonylmethane (MSM), Minerals, Naringin, Pancreatin, Para-aminobenzoic Acid (PABA), Paraben (methyl or propyl), Phenolics, Phosphatidylcholine (Lecithin), Phosphatidylserine, Phospholipids, Phytosterols, Progesterone, Pregnenolone, Resveratrol, D-Ribose, Rutin, S-adenosylmethionine (SAM-e), Salicylic Acid, Sulforaphane, Tartaric Acid, Taxifolin, Tetrahydropalmatine, Thephyline, Theobromine, Tigogenin, Troxerutin, Tryptophan, Tocotrienol (alpha, beta & gamma), Vitamins, Zeaxanthin, Ginkgo Biloba, Ginger, Cat's Claw, Hypericum, Aloe Vera, Evening Primrose, Garlic, Capsicum, Dong Quai, Ginseng, Feverview, Fenugreek, Echinacea, Green Tea, Marshmallow, Saw Palmetto, Tea Tree Oil, Payllium, Kava-Kava, Licorice Root, Manonia Aquifolium, Hawthorne, Hohimbr, Tumeric, Witch Hazel, Valerian, Mistletoe, Bilberry, Bee Pollen, Peppermint Oil, Beta-Carotene, Genistein, Lutein, Lycopene, the Polyphenols (bioflavonoids), and the like.

In some embodiments, a nutraceutical may include microbes (i.e., probiotics). Examples of such microbes include, but are not limited to, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei, Bifidobacterium bifidum, Bifidobacterium longum, Saccharomyces boulardii, Saccharomyces cerevisiae, and the like (Samuel and Gordon, PNAS, 103(26): 1001 1 - 10016 (2006)). In some embodiments, a nutraceutical may include non-living microbes. For example, non-living Saccharomyces cerevisiae may be used as a source of vitamin B 12. In some embodiments, recombinant microbes may be utilized as nutraceuticals. For example, in some embodiments, microbes may be genetically modified to produce, or overexpress, one or more nutraceuticals.

The nutraceuticals may generally be prescribed on a predetermined individualized program based, for example, on the blood profile of an individual who has been diagnosed with a cancer such as pancreatic cancer. After the initial period, the blood test(s) may be repeated and adjustment made to the nutraceutical regimen, both as to the component compounds and their dosages. The nutraceuticals are specifically blended to address the specific deficiencies detected in the patient's blood and are precisely dosed accordingly based on, for example, the patient's weight, age, sex, and/or severity of the imbalances or deficiencies intended to be addressed by the nutraceutical. One skilled in the art, for example a patients oncologist or primary care physician, following analysis of, for instance, blood samples from the affected patient, will be able to determine the precise combination of nutraceuticals and the proper dosages of each compound.

The nutraceutical combination may be administered in any form, preferably as a tablet, powder, or liquid, formulated into a pharmaceutically acceptable carrier or excipient, depending on the condition of the patient. Providing such custom tailored dosages eliminates the need for pre- formulated capsules and tablets. Additionally, non-active ingredients well known in the art, such as binders, fillers, coatings, preservatives, coloring agents, flavoring agents and other additives may optionally be formulated with the composition or left out completely if there is a risk of negative side effects to the patient such as increased the risk of intestinal inflammation or interference with the absorption of the compounds.

The compositions of the present invention may also include, in addition to nutraceutical compounds, any of a number of non-chemotherapeutic drugs for their desired effects on metabolic or signaling pathways. Such non-chemotherapeutic drugs may address the same pathway(s) as nutraceutical components of a composition of the invention or may address pathways not adequately altered by administration of the nutraceutical components. As these components are drugs and thus subject to regulations, they normally may only be included by order of a physician or qualified and licensed healthcare practitioner. Such non-chemotherapeutic drugs include but are not limited to Metformin, Celebrex, Naltrexone, Tetrathiomolybdate, Melatonin, and others. The use of non- chemotherapeutic drugs in the compositions of the invention is discussed further infra.

In the case pancreatic cancer, a specific goal of the individualized nutraceutical/non- chemotherapeutic drug program described herein includes shrinkage of a pancreatic cancer or tumor to a level where the patient becomes a candidate to undergo a Whipple procedure, which is an extremely safe operation (mortality rate < 4% in the U.S.) whereby the head of the pancreas (in the case of pancreatic cancer), is surgically removed.

For many of the nutraceutical compounds and non-chemotherapeutic pharmaceutical agents disclosed herein, there are a number of equivalent agents that will be known to those skilled in the art. A list of preferred nutraceuticals and non-chemotherapeutic pharmaceutical agents for use in the methods and compositions disclosed herein and their equivalents are discussed below:

Acetyl L-Carnitine

Acetyl L-Carnitine (ALC) is an amino acid naturally produced in the body to help convert glucose to energy. It is in a highly bioavailable form of the L-Carnitine ether antioxidant that is more readily absorbed and helps the body make better use of other antioxidants, such as vitamins C and E, and coenzyme Q 10. It is also referred to by the following: Acetil-L-Carnitina, Acetyl Carnitine, Acetyl Carnitine, Acetyl L-Carnitine, Acetyl-L-Carnitine, Acetyl-L-Carnitine Arginate

Dihydrochloride, Acetyl-L-Carnitine Arginate HC1, Acetyl-L-Carnitine Arginate HC1, Acetyl-L- Carnitine HC1, Acetyl-L-Carnitine HC1, Acetyl L-Carnitine Hydrochloride, Acetyl Carnitine, Acetyl- Carnitine, Acetyl-Levocarnitine, Acetyl-Levocamitine, ALC, Alcar, Carnitine Acetyl Ester, Dihydrochlorure d'Acetyl-L-Carnitine Arginate, Gamma-Trimethyl-Beta-Acetylbutyrobetaine, L- Acetylcarnitine, L-Acetylcarnitine, Levacecarnine, N-Acetyl-Carnitine, N- Acetyl-Carnitine, N- Acetyl-L-Carnitine, N-Acetyl-L-Carnitine, ST-200, Vitamin B(t) Acetate, 2-(acetyloxy)-3-carboxy- Ν,Ν,Ν-trimethyl- 1 -propanaminium inner salt; (3 -carboxy-2-hydroxy -propyl) trimethylammonium hydroxide inner salt acetate.

ALC plays a key role in energy metabolism and stress response by assisting in the transport of fat through the cell membrane and into the mitochondria. ALC has been shown to be effective in enhancing the antitumor potential of platinum compounds (e.g., neurotoxic chemotherapy reagent cisplatin) in tumors as well as increased antimetastatic activity. In addition, ALC has been shown to effectively inhibit the increase in cisplatin-induced oxidative glutathione and, as such, is a useful agent in preventing toxicity within tumor cells and oxidative injury.

The best external source of Acetyl L-Carnitine is a supplement of Acetyl-L- Carnitine and the commercially available form is Life Extension Acetyl-L-Carnitine available in 1000 mg per serving. NutraBio Acetyl-L-Carnitine is also available at 99.88% purity. In addition, there are several other commercially available Acetyl-L-Carnitine products including Swanson's Premium Acetyl-L- carnitine, Twinlab Acetyl-L-carnitine, NOW Foods Acetyl-L-carnitine, Jarrow Acetyl-L-carnitine, Source Naturals Acetyl-L-carnitine & Alpha-Lipoic Acid, Nature's Bounty Acetyl-L-carnitine, and Nature's Way Acetyl-L-carnitine.

An alternative compound for ACL is L-carnitine. L-carnitine does not cross the blood brain barrier as readily as ACL, but in vivo L-carnitine is converte into Acetyl L-Carnitine.

Alpha-Lipoic Acid

Alpha-Lipoic Acid is a fatty acid produced by the body for converting glucose into energy. It is also known to have antioxidant properties beneficial for fighting harmful chemicals that contribute to onset of disease. It is also referred to by the following names: Acetate Replacing

Factor, A-Lipoic Acid, Acide Alpha- Lipoi^'que, Acide Alpha- Lipoi^'que R, Acide DL-Alpha-Lipo^'ique, Acide Lipoi^'que, Acide Thioctique, Acide l ,2-dithiolane-3-pentano^'ique, Acide l ,2-dithiolane-3- valerique, Acide 5 Valerique (l ,2-dithiolan-3-yl), Acide 6,8-dithiooctano^'ique, Acide 6,8-Thioctique, Acido Alfa Lipoico, Alpha-Lipoic Acid Extract, ALA, Biletan, Extrait d' acide Alpha-Lipoi^'que, Lipoic Acid, Lipoicin, R-ALA, R- Alpha- Lipoic Acid R, S- Alpha Lipoic Acid, (R)-Lipoic Acid, R- Lipoic Acid, RS-Alpha-Lipoic Acid Thioctacid, Thioctan, Thioctic Acid, l ,2-dithiolane-3-pentanoic acid, 1 ,2-dithiolane-3 -valeric acid, 6,8-dithiooctanoic acid, 6,8-thioctic acid, 5-(l ,2-dithiolan-3-yl) valeric acid.

Although manufactured by the body and found in trace amounts in foods such as spinach, broccoli, peas, Brewer's yeast, brussel sprouts, rice, bran, potatoes and organ meats (kidney, heart, liver), it is the concentrated amounts of Alpha-Lipoic Acid found in supplements that provides the best antioxidant effect. When produced endogenously in plants or humans, it is complexed with proteins. However, when taken in supplement form, it is not bound to proteins and is likely in a 1000 fold greater amount than can be obtained through regular diet.

Alpha-Lipoic Acid is known to inhibit TNF-a-induced NF-kappaB pathway activation which leads to endothelial activation and monocyte adhesion, which are the initial steps to leading to inflammation caused by oxidative stress. Alpha-Lipoic Acid has also been found to inhibit copper- and iron-mediated oxidative damage and accumulation via chelation of free metal ions. This process suppresses the induced oxidative damage caused by reactions that produce reactive free radicals. The addition of Alpha-Lipoic Acid to cultured cells has been shown to activate PKB/Akt-dependent signaling resulting in increased survival of neurons.

Several Alpha-Lipoic Acid supplements are presently manufactured. It is important to note that Alpha-Lipoic Acid contains an asymmetric carbon, meaning there are two possible optical isomers that are mirror images of each other (R- and S-isomers). Most supplements may contain a 50/50 racemic mixture of each R-Alpha-Lipoic Acid and S- Alpha-Lipoic Acid. Supplements that contain only the R-isomer are available but the level of purity may be uncertain. Since taking Alpha- Lipoic Acid with a meal decreases its bioavailability, it is generally recommended that it be taken on an empty stomach (one hour before or two hours after eating).

Commercial suppliers for ALA include Source Naturals Alpha Lipoic Acid, Swanson Ultra Alpha Lipoic Acid, NOW Foods Alpha Lipoic Acid, Bluebonnet Alpha Lipoic Acid, Country Life R- Lipoic Acid, Solgar Alpha Lipoic Acid.

Apigenin

Apigenin is a dietary flavonoid common in fruits and vegetables. It is also known as biapigenin (a dimer found in nature) or 4',5,7-trihydroxyflavone.

Apigenin inhibits the Hedgehog signaling pathway. Apigenin additionally monitors immune cells in inflammation and cell proliferation by promoting cell death via inhibition of NF-κΒ pathway activation and suppression of NF-KB-regulated anti-apoptotic molecules. Apigenin selectively inhibits PI3K-PKB/Akt, to increase activation induced cell death. Apigenin also suppresses expression of anti-apoptotic cyclooxygenase 2 (COX-2) protein in activated human T cells, but does not affect activation of Erk MAP Kinase.

Apigenin plays a key role in reducing levels of the insulin- like growth factor, IGF- 1 , a protein that promotes tissue growth and is linked to increased risk of certain cancers including prostate, breast, colorectal and lung cancers. Increased IGF signaling stimulates proliferation and inhibits apoptosis in cancer cells, so the use of apigenin is beneficial for its anti-proliferative effect. Activation of phosphatidylinositol 3 -kinase- Akt signaling pathway contributes to the development of several malignancies. Treatment with apigenin is shown inactivate the Akt pathway through downregulation of insulin-like growth factor receptor 1 proten levels which also reduces survival of cancerous cell lines in a dose-dependent manner.

In addition, Apigenin has been shown to inhibit cell proliferation and VEGF expression and transcription of cancer cells in the low micromolar range. The down-regulation of hypoxia response genes HIF- 1 a, GLUT- 1 and VEGF caused by apigenin has been shown to exhibit anti-pro liferative and anti- angiogenic activity in pancreatic cells. Additionally, apigenin has been shown to inhibit the growth of pancreatic cancer cells through suppression of cyclin B-associated cdc2 activity and G2/M arrest. Tumor necrosis factor alpha (TNFa) is a cytokine involved in the expression of many genes integral to the inflammatory response. It activates both survival pathways through the activation of the transcription factor NFkappaB as well as apoptotic pathways. Apigenin, in conjunction with TNF-a, effects the reduction of cell survival and colony proliferation.

Apigenin is commercially available in supplement form, specifically, Swanson Ultra Apigenin derived from grapefruit. It is also commonly isolated in abundance from Matricaria recutita L, or Asteraceae. Supplements with 98% pure apigenin are more effective than lower concentrations.

Alternatives to apigenin may be found in foods such as parsley, thyme, peppermint, tarragon, cilantro, foxglove, coneflower, licorice, flax, passion flower, horehound, spearmint, basil, oregano, celery, grapefruits, oranges, apples, beans, broccoli, cherries, leeks, onions, grapes, tomatoes, tomato sauce, tea, chamomile herb, perilla herb, berbain herb, yarrow, horsetail herb, and red wine. It is absorbed in small amounts through consumption of these foods, but does not reach the concentration of absorption in blood possible with supplements due to low bioavailability. Extracts of many of these foods are available, especially chamomile extract (Nature's Way Chamomile contains 1.2% apigenin), Life Extension's Triple Action Cruciferous Vegetable Extract Apigenin (also contains broccoli extract, Indole-3 carbinol, DIM, and carnosol).

Chinese Skullcap (Scutellaria baicalensis)

Baicalin and baicalein are the primary derivatives of the Chinese Skullcap herb {Scutellaria baicalensis), a member of the lamiaceae (mint) family native to China. It contains 95% baicalin and flavonoids. It is also referred to as: Baikal Scullcap, Baikal Skullcap Root, Chinese Skullcap, Escutelaria Asiatica, Huang Qin, Huangquin, Hwanggum, Ogon, Ou-gon, Racine de Scutellaire du Lac Baikal, Radix Scutellariae, Scullcap, Scute, Scutellaire, Scutellaire Chinoise, Scutellaire du Lac Baikal, Scutellaria, Scutellaria baicalensis, Scutellaria macrantha, Scutellariae Radix, Skullcap, Wogon.

The active ingredient baicalein is more potent than baicalin for promoting anti-angiogenesis. Taken together, results show that baicalein and baicalin possess anti-angiogenesis potential. Baicalin is a potent anti- angiogenic compound that reduces VEGF, bFGF, 12-lipoxygenase activity, and

MMP. Both baicalein and baicalin exhibited antiproliferative (at low dose) and apoptogenic (at high dose) effects on human umbilical vein endothelial cells (HUVECs). In addition, migrations and differentiation of endothelial cells is inhibited by these compounds. Baicalein inhibited COX-2 and NF-KB/p65 expression, but stimulated HIF- 1 a expression. Therefore, its inhibitory action is believed to be due to the expression of MMP-9 and VEGF through the suppression of COX-2 and NF-KB/p65 expression. Baicalin also inhibits the production of other inflammatory cytokines including IL-6, IL-

8, and MCP- 1 through inhibition of NF-κΒ activation. In addition, Baicalein also inhibits the Hedgehog signaling pathway, as well as the PDGF-BB-stimulated vascular smooth muscle cell proliferation through the suppression of the PDGFRJ3-ERK signaling pathway.

The best source of baicalin and baicalein is Chinese Skullcap. This is commercially available from New Chapter's Chinese Skullcap available in 17-26% Baicalein (34+mg/200mg capsule). New Chapter's Chinese Skullcap Force™ (5: 1 ratio) and Swanson Premium Full Spectrum

Chinese Scullcap (4: 1 ratio) are other acceptable sources.

Alternatively, multipurpose supplements often contain trace amounts of Chinese Skullcap to support liver function, enhance immune function, combat allergies, and relieve general aches and pains (e.g. Gaia Herbs: Aller-leaf, Candida Cleans, Flora Wellness, Liver Health). However, the trace amounts available in these supplements makes the concentration of baicalein and baicalin out of the clinically effective range suitable for practicing the present invention.

Boswellia

The active ingredients in Boswellia are boswellic acids (Acetyl- 1 1 -keto-beta-boswellic acid (AKBA), beta-boswellic acid, acetyl-alpha-boswellic acid, acetyl-beta-boswellic acid, and betulinic acid) extracted from the Boswellia serratta tree. The extract is known to have anti- carcinogenic, anti-tumor, and blood cholesterol and trigylceride activities.

Boswellic acids inhibit active NF-κΒ and suppress NF-κΒ gene expression. They also induce apoptosis, and sensitize the cells to apoptotic effects of certain chemotherapies such as gemcitabine. They also inhibited metastasis in pancreatic cancer studies which correlated with proliferative biomarkers. They have been shown to downregulate the expression of COX-2, MMP-

9, CXCR4, and VEGF in the tissues. Overall these results indicate that boswellic acids are effective at suppressing the growth and metastasis of human pancreatic tumors.

It has been determined that supplements made from AKBA provide the most effective boswellic acids. Other boswellia-derived compounds partially or incompletely inhibit inflammation- provoking enzymes (e.g. 5-lipoxygenase).

The best source of boswellic acid is from Boswellia. Most beneficially, extract potencies of viable supplements should contain at least 65% Boswellic Acids. The bioavailability of boswellic acid is improved when taken with food. Source Natural's Boswellia Extract is formulated to contain at least 70% boswellic acids as is Pure Encapsulations Boswellia. Other sources include Nature's Way Boswellia, NOW Foods Boswellia Extract Double Strength, Solaray Boswellia, Swanson Premium Boswellia, Puritan Pride Boswellia Extract and GNC Herbal Plus Boswellia, which all have at least 65% boswellic acids.

Alternatively there are supplements that are not as highly concentrated with boswellic acids. For example, Swanson Superior Herbs Boswellia Serrata (Standardized) contains 20% boswellic acids and 70% other organic acids. The Vitamin Shoppe Boswellia Serrata Standardized Extract contains 65-70%) total organic acids, including boswellic acids. Life Extension has a patent-pending, standardized form of boswellia called ApresFlex™ that is being introduced and is supposedly capable of absorbing into the blood 52% better than previously available boswellia extracts (still only providing 20% active AKBA from Boswellia).

Co-Enzyme Q 10

Coenzyme Q- 10 (CoQ- 10) is a vitamin- like substance found throughout the body, mostly in the heart, liver, kidney, and pancreas. It is available in small amounts in meats and seafood.

Coenzyme Q- 10 can also be synthesized in the laboratory in pharmaceutical-quality for medicinal purposes. It is also referred to as Co Q10, Co Q-10, Coenzima Q-10, Co-Enzyme 10, Coenzyme Q 10, Coenzyme Q10, Co-Enzyme Q10, Co-Enzyme Q-10, Co-Q 10, CoQ 10, Co-QlO, CoQ- 10, Ubidcarenone, Ubidecarenone, and Ubiquinone- 10.

The most bioavailable form of CoQ 10 is ubiquinol, which is a breakdown product of CoQ 10. Over 90% of the CoQ 10 in the body is in the form of ubiquinol. Ubiquinol is the active antioxidant form of CoQ 10.

Ubiquinol is known to inhibit the expression of VEGF. It was demonstrated that coenzyme Q, in addition to its role in electron transport and proton transfer in mitochondrial and bacterial respiration, acts in its reduced form (ubiquinol) as an antioxidant, recycling radical forms of vitamin C and E, and protecting membrane phospholipids against peroxidation, which suggests an important role in cellular defense against oxidative damage. Neurodegenerative disorders, cancer, cardiovascular diseases, diabetes mellitus, and especially aging, and Alzheimer's disease exhibit altered levels of ubiquinone or ubiquinol, indicating their likely crucial role in the pathogenesis and cellular mechanisms of these disorders.

The most beneficial form of CoQ 10 is ubiquinol. This is commercially available as Kaneka QH™. Kaneka's Ubiquinol achieves higher levels of circulating CoQ 10 in the bloodstream with just a fraction of the dose required when using a regular CoQ 10 supplement. Swanson Ultra's Ubiquinol 100% Pure & Natural is produced from 100% natural CoQ 10 through a biological fermentation process with Kaneka QH™ Enhanced Bioactivity CoQ 10. Pure encapsulation also uses the Kaneka QH™. Life Extension Super Ubiquinol CoQ 10 offers a highly bioavailable ubiquinol form of CoQ IO that is a novel solubilized formulation of CoQIO (Solu Q 10) in a patented delivery system with superior absorption levels.

Alternate supplements to Ubiquinol would be CoQ IO in pure form, although this is less effective. Commercial forms for CoQIO are available through Swanson Ultra CoQIO, NatureMade CoQ IO, Twinlab CoQ Ultra, and supplements such as Doctor's Best High Absorption CoQIO with Bioperine.

Curcumin

The active ingredient in the spice Turmeric is curcumin, which is extracted from the rhizome of the plant curcuma longa Linn. Curcumin is the principal curcuminoid, or polyphenolic compound, with others including demethoxycurcumin and bisdemethoxycurcumin.

Turmeric is also known as Curcuma, Curcuma aromatica, Curcuma domestica, Curcumae longa, Curcumae Longae Rhizoma, Curcumin, Curcumine, Curcuminoid, Curcumino^'ide,

Curcuminoi^'des, Curcuminoids, Halada, Haldi, Haridra, Indian Saffron, Nisha, Pian Jiang Huang, Racine de Curcuma, Radix Curcumae, Rajani, Rhizoma Cucurmae Longae, Safran Bourbon, Safran de Batallita, Safran des Indes, Turmeric Root, Yu Jin.

Curcumin's mechanisms of action include inhibition of several cell signaling pathways, effects on cellular enzymes such as cyclooxygenase and effects on angiogenesis and cell-cell adhesion. Curcumin also affects gene transcription and induces apoptosis.

Curcumin is effective at inhibiting the signal transduction pathway of PI3K/Akt, MAPK, and NF-κΒ activation, as well as the Sonic Hedgehog (Shh) signaling pathway by down-regulating the Shh protein. In turn, reduction of beta-catenin, the activated/phosphorylated form of Akt and NF- KB, triggers apoptosis.

The oncogenic pathways inhibited by curcumin include down-regulation of epidermal growth factor receptors (EGFR and erbB2), Insulin- like growth factor type- 1 receptor (IFG-1R), sonic hedgehog (SHH)/GLIs) and Wnt/b-catenin and PARP, IKK, EGFR, JNK, MAPK and 5-LOX. In addition curcumin suppresses downstream signaling elements such as signal transducers and activators of transcription (STATs), PI3K/Akt, nuclear factor-kappa B (NF-κΒ), and its targeted genes, including IL-6, COX-2, and MMPs.

Curcumin is most beneficial when take in liposomal form. The most bioavailable supplement is Life Extension's Super Bio Curcumin® which absorbs into the bloodstream up to seven times better than conventional 95% curcumin extract. Other curcumin supplements add piperine, (Piper nigrum) to enhance absorption of curcumin in their products. However, the interactions of piperine with many medications can cause problems including toxicity if taken in high doses. Curcumin can exist in the tautomeric forms that include the 1,3-diketo and the enol form. The most stable form of Curcumin is its planar enol form. Additionally Biomar™ Curcumin is commercially available. Alternatives to Super Bio-Curcumin® include all 95% Curcumin supplements including Jarrow Formulas Curcumin 95, NOW Foods Curcumin, Genceutic Naturals Curcumin BCM-95, etc. Turmeric Extract in fact only provides 2-6% curcumin, so it is important to take curcumin in higher levels. Any supplement that is lower than 95% Curcumin is not as effective. Only about 50-60% is absorbed (in contrast to 96% absorption with Super Bio Curcumin®). In addition, dilutions with other supplements such as bioperine reduce bioavailability, and as mentioned piperine can interact with other medications negatively. Synthetic, petroleum-derived curcumin supplements may only contain on or two of the important curcuminoids found in natural supplements. Resveratrol is not a substitute. There are "Ultimate Antioxidants" that contain Curcumin and other important antioxidants, but do not reach the quality or bioavailability of other supplements (e.g. Natural

Factors®Ultimate Antioxidant is only claims 95%total curcuminoids, but does not specify which, and has 13 other factors to contend with.

Fucoidan

Fucoidan, (common name sulfated alpha-L-fucan), is a sulfated polysaccharide found in the cell walls of many brown seaweeds. Fucoidan is known to induce apoptosis of human Lymphoma HS-sultan cells through activation of caspase-3 and down-regulation of ERK pathways.

Fucoidan has also been shown to inhibit metastasis by preventing adhesion of tumor cells to the extracellular matrix. This is achieved by blocking the fibronectin cell-binding domain. Fucoidan was also shown to induce apoptosis of human T-cell leukemia virus type I by inactivating NF-kB that regulates antiapoptotic proteins. Fucoidan is also known to enhance the activity of NK cells. Also, p38 MAPK, AP- 1 , JAK/STAT and IRF- 1 play an important role in the inhibitory effect of fucoidan on TNF-alpha- and IFN-gamma-stimulated NO production in C6 glioma cells.

Fucoidan is found primarily in edible seaweeds such as mozuku, kombu, limu moui, bladderwrack, wakame and hijiki, as well as brown algae. A single vegetarian capsule of Optimized Fucoidan with Maritech 926 provides 88.5 mg of standardized (85% organic fucoidan) Undaria pinnatifida extract, the more preferred seaweed species, equaling the amount of fucoidan typically consumed daily in the traditional Japanese diet. Swanson GreenFoods Fucoidan is made from Laminaria japonica and Cystoseira canadensis brown seaweed and includes up to 40% total polysaccharides and 5% seaweed phenolics.

Genistein

Genistein is an isoflavone extracted from fermented soy. It is also referred to as

Basidiomycetes Polysaccharide, Fermented Genistein, Fermented Isoflavone, GCP, Genistein Polysaccharide, Genisteine du Polysaccharide Combine, Isoflavone Combined Polysaccharide, Polysacaridos Combinados de Genisteina, and Soy Isoflavone Polysaccharide

Genistein plays an important role in reducing the incidence of breast and prostate cancers. It has been shown that genistein inhibits the activation of NF-kappaB and Akt signaling pathways, both of which are known to maintain a homeostatic balance between cell survival and apoptosis.

Furthermore, genistein has been found to have antioxidant properties, and shown to be a potent inhibitor of angiogenesis and metastasis. In addition, genistein works to target endogenous copper which leads to pro-oxidant signaling and consequent cell death.

Genistein has also been shown to downregulate the IGF-1/IGF-1R signaling pathway and inhibit cell growth in hormone refractory PC-3 prostate cancer cells. Treatment with Genistein resulted in a significant inhibition of IGF- 1 -stimulated cell growth. Treatment with Genistein also strongly attenuated IGF- 1 -induced β-catenin signaling that correlated with increasing the levels of E-cadherin and decreasing cyclin Dl levels in PC-3 cells. In addition, genistein inhibited T-cell factor/lymphoid enhancer factor (TCF/LEF)-dependent transcriptional activity.

Genistein has also been shown to inhibit VEGF-induced endothelial cell activation by decreasing PTK activity and MAPK activation, resulting in anti-angiogenic activity. Exposure to genistein also decreased activation of J K and p38, not ERK-1/2, induced by VEGF. It also inhibited activity of MMPs.

Genistein is readily bioavailable. The purest form is commercially available in 99% purity from laboratories including LC Labs, Enzo Life Sciences, BioVision. However, not all forms are suitable for human consumption. Less preferable sources are the soy isoflavone supplements that contain genistein at lower concentrations.

Graviola

The active ingredients in Graviola are known as annonaceous acetogenins and are isolated from the leaves, bark and twigs of graviola. The Graviola tree (Annona muricata) is most commonly also known as sour sop. In addition it is also referred to as Brazilian Cherimoya, Brazilian Paw Paw, Corossol epineux, Corossolier, Durian Benggala, Guanabana, Guanavana, Nangka Blanda, Nangka Londa, Soursop, Sour Sop, and Toge-Banreisi.

Extracts of graviola have demonstrated antiviral, antirheumatic, and anti-inflammatory properties. Graviola is also effective against multidrug resistant cancer cell lines. Graviola extracts are also effective against the growth of Adriamycin-resistant human mammary adenocarcinoma (MCF-7/Adr) by blocking the access of the cancer cell to ATP and thereby inhibiting the actions of plasma membrane glycoprotein. Graviola fruit extract (GFE) significantly downregulates EGFR gene expression and inhibits the growth of BC cells and xenograft.

The more preferred supplements that are derived from Graviola are Graviola leaf powder, Soursop leaf, Graviola leaf and steam (soursop), and Annona muricata in a capsule.

Green Tea Extract (EGCG Green Tea Extract contains health-promoting polyphenols, primarily epigallocatechin-3- gallate (EGCG), a powerful antioxidant known to inhibit growth, and induce apoptosis in human pancreatic cancer cells. Other catechins include EC, ECg, and EGC.

EGCG has been shown to inhibit the Hedgehog signaling pathway. It also inhibits VEGF- induced growth and migration of cells and decreases VEGF binding to its receptor, affecting the downstream VEGF signaling pathway. Other tea catechins have not been shown to inhibit VEGF binding. High levels of EGCG inhibit NFKB activation in several types of cancer. Furthermore, EGCG suppresses oxidant-induced production of the proangiogenic cytokine interleukin (IL)-8. EGCG also plays a key role in apoptosis of cancer cells by H202-stimulated COX-2 expression via the AMPK signaling pathway, reducing EGFR signaling and cellular proliferation, reducing ERK activity and enhancing p38 and JNK activities. In addition EGCG has also been shown to inhibit P13K/AKT and MEK/ERK pathways to enhance its antiangiogenic effect.

The best commercial source for EGCG is Life Extension Mega Green Tea (Decaf or lightly caffeinated) which contains 98% green tea extract for increased potency (98% total polyphenols and 45% EGCG). Similarly, Swanson Superior Herbs Teavigo® Green Tea Extract 90% EGCG contains up to 90% EGCG.

Slightly less effective supplements include, Swanson Green Tea Extract which is includes up to 60% polyphenol concentration, Swanson Ultra EGCG Super Strength Green Tea which includes up to 40% EGCG, NOW Foods Green Tea Extract which includes 60% polyphenols, or NOW Foods EGCG Green Tea Extract which contains 98% total polyphenols, 80% total catchins, and 50% EGCG.

An alternative to Decaf and lightly caffeinated is caffeinated green tea extract. Piperine has also demonstrated increased bioavailability, but interactions with other medications negatively impact the overall blood chemistry. All green tea extracts should be checked for EGCG content. Enzymatic Therapy produces a Green Tea Elite with EGCG that has Leaf Phytosome™, a combination of one part Green Tea Extract standardized to contain 60% polyphenols and 40% EGCG, and a diltution with two parts phosphatidycholine (soy). There are "Ultimate Antioxidants" that contain EGCG and other important antioxidants, but do not reach the quality or bioavailability of other supplements (e.g. Natural Factors®Ultimate Antioxidant is only standardized to 13% EGCG and contains Phytosome® with soy).

Grape Seed Extract

The active ingredient in Grape Seed Extract is proanthocyanadin and possesses

antiangiogenic activity. The antiangiogenic mechanism underlying Grape Seed Extract is its inhibition of VEGF messenger RNA (mRNA) expression by reduction of HIF-1 alpha protein synthesis through blocking Akt activation. Grape Seed Extract also upregulates IGFB-3, further indicating antiproliferative, proapoptotic, and antiangiogenic activity. Grape Seed proanthocyanidins have also been shown to suppress levels of COX-2, cyclin D 1 , proliferating cell nuclear antigen, inflammatory cytokines, TNF-a, IL- 1 β and IL-6, when tested in melanomas. Grape seed extract inhibits EGF-induced signaling and activates JNK in a dose- dependent manner leading to more antiproliferative and apoptotic effect.

Grape Seed Extract has been patented as Traconol™. This is a hybrid grape seed extract that exhibits triple the antioxidant activity of generic grape seed extracts with 95% pure oligomeric proanthocyanidins (OPCs). However, in addition to this patented version, other supplements that contain 95% OPCs include Jarrow Formulas OPCs+95 Grape Seed Extract, Kroeger Labs Grape Seed Extract, Natural Factors Grape Seed Extract, etc.

There is currently a demand for nonspecific "grape seed extracts" that contain grape seeds that have not gone through the extraction process, or ground grape components, (e.g. Olympian Labs Grape Seed Extract contains ground up seeds and skins and other contaminants of red grapes).

Alternatively there are "Ultimate Antioxidants" that contain Grape Seed and other important antioxidants, but do not reach the quality or bioavailability of these supplements (e.g. Natural Factors®Ultimate Antioxidant Grape Seed Phytosome®, which contain soy and is standardized to contain 85 to 95% leucoanthocyanins (proanthocyanidins), bound to phosphatidylcholine from lecithin). It is also possible to get Grape Seed Phytosome® alone, but that is still not as bioavailable. Flavay® is a proanthocyanidins complex, isolated from Vitis vinifera seed and Pinus maritime French pine bark. However, it also contains undesirable enzyme contaminants (Macrozyme™). In addition to grape seed derivatives, Pycnogenol, derived from pine bark extract, is a slightly less bioavailable, and slightly more expensive alternative to grape seed extract. [See section on pycnogenol for additional information]. Grape seed oil is not an alternative as proanthocyanidins are not detected therein. Resveratrol, although being a grape-derived dietary supplement found in the skin of grapes (also found in peanuts, mulberries, red wine extracts and polyugonum csupidatum), acts differently as it is an antioxidant. Many supplements of Grape Seed extract will contain resveratrol in addition (e.g. Life Extension Grapeseed Extract with Resveratrol & Pterostilbene) which have highly bioavailable function, but act differently than grapeseed extract alone.

Medizym® enzyme blend

Medizym is a natural, drug-free systemic enzyme formula suitable for immune system and inflammation normalization support. It contains proteases, enzymes that breakdown proteins.

Enzymes seem to help maintain normal growth factor activities as well. However, when these activity levels rise, so do scarring and fibrosis. Studies show proteolytic systemic oral enzymes reduce levels of transforming growth factor-beta. Medizym is capable of keeping levels of TNF-a, IL-6, and C-reactive protein within a healthy normal range. In addition, aggressive nutritional therapy with large doses of pancreatic enzymes has been shown to significantly increase survival over what would normally be expected for patients with inoperable pancreatic adenocarcinoma. Medizym is a very effective way for administration of proteolytic enzymes. There are two different Medizym supplements: The Systemic Enzyme Formula contains Pancreatin (pancreas protease Sus scroga), Papain (Carica papaya), Bromelain (Ananas comosus), Trypsin (pancread Sus scrofa), Chymotrypsin (pancreas Sus scrofa), and Rutosid (Sophora japonica); The Vegetarian Enzyme Formula contains Papain (Carica papaya), Bromelain (Ananas comosus), and Rutosid (Sophora japonica).

Alternative sources for the individual components that combine to create Medizym include: Raw and fermented foods like honey, vegetables, fruits and yogurt, which provide proteolytic enzymes which may be absorbed internally. The components in Medizym come together to provide a wide range of these enzymes in one formula. Bromelain is derived from the pineapple plant

(Ananas comosus). Papain is derived from the unripe fruit of the Carica papaya, commonly known as the Papaya. Trypsin, Chymotrypsin, and Pancreatin (enzyme mixture) are pancreatic-sourced enzymes that are porcine and calf-derived. Rutin (rutosid, quercetin-3-rutinoside or sophorin, ferulic acid) is a citrus bioflavonoid derived from Sophora japonica, but also found in buckwheat, the fruit of the Fava D'Anta tree in Brazil, and possible other sources.

It is important to replenish pancreatic enzymes when the pancreas is under severe stress and cannot produce them on its own. Supplemental pancreatic enzymes are available in prescription and non-prescription forms. The different brands of pancreatic enzyme products are not identical. Over- the-counter pancreatic enzyme products are available without a prescription. Approved sources of pancreatic enzymes for prescription include Creon® capsules, Pancreaze™ capsules and Zenpep™ capsules. Those pending FDA approval include Pancrecarb® capsules, Ultrase® tablets and Viokase® tablets or powder.

Melatonin

Melatonin is a hormone secreted by the pineal gland and found naturally in the body.

Melatonin is also synthetically produced in a laboratory for medical use. It is also referred to as MEL, Melatonina, Melatonine, MLT, N-acetyl-5-methoxytryptamine, N-Acetyl-5- Methoxytryptamine, and Pineal Hormone.

Melatonin is known to suppress tumor angiogenesis by inhibiting HIF- 1 a stabilization under hypoxia, leading to a decrease in VEGF expression. Melatonin also inhibits cell proliferation and migration of HUVECs and also decreases both the VEGF protein secreted and the protein produced by pancreatic carcinoma cells. In addition, VEGF mRNA expression is known to be down-regulated by melatonin. Melatonin has also been shown to inhibit cell proliferation and induce apoptosis in cancer cells in vitro by simultaneously suppressing the COX-2/PGE2, p300/NF-KB, and

PI3K/Akt/signaling and activating the Apaf- l/caspase-dependent apoptotic pathway.

The most beneficial form of Melatonin is in pharmaceutical grade (not "natural", animal, or bovine) supplements having a purity of 99% or greater. The bioavailability of melatonin varies widely. Melatonin has several clinical analogs that bind to melatonin receptors, but ultimately have a different function (most commonly as a sleep aid only or antidepressant only). These include S20242, agomelatine, and 2-Bromomelatonin. When melatonin, ramelteon, tasimelteon, PD-6735, and agomelatine are compared, agomelatine is the analogue that exhibits the most potential for the treatment of major depression. Unlike melatonin, agomelatine is a competitive antagonist of human and porcine serotonin (5-HT2C) receptors and human 5-HT2B receptors.

Alternatively, there are medications that include impurities and low levels of melatonin, for example, Circadin used for insomnia. Melatonin should only be taken in synthetic (man-made) form. The alternative that is extracted from ground-up cow pineal glands is rarely used, as it may spread disease.

Metformin

Metformin is a pharmaceutical compound initially indicated for diabetes and has the following brand names: Glucophage, Riomet®, Fortamet, Glumetza. Metformin modulates the mTOR pathway, which antiproliferative effects during treatment with paclitaxel. Metformin also functions in reducing cell growth, protein synthesis, MAPK3/1, and P90RSK phosphorylation in response to IGF1 through an AMPK-dependent mechanism in cultured bovine granulosa cells. In addition. Metformin strongly inhibited the proliferation, migration, and MMP-2 and -9 expression of HUVECs, also partially AMPK-dependent. Metformin also inhibits cell proliferation, migration and invasion through reexpression of miRNAs and decreased expression of CSC- specific genes, which suggests that Metformin could be useful for overcoming therapeutic resistance of pancreatic cancer cells.

There are two main lines of evidence that suggest that Metformin's primary target is the immortalizing step during tumorigenesis. First, Metformin activates intracellular DNA damage response checkpoints. Second, Metformin attenuates the anti-senescence effects of the ATP- generating glycolytic metabotype, i.e., the Warburg effect, which is required for self-renewal and proliferation of CSCs. If Metformin therapy presents an intrinsic barrier against tumorigenesis by lowering the threshold for stress-induced senescence, it is expected that Metformin therapeutic strategies may be pivotal for therapeutic intervention for cancer.

Sources of Metformin include Metformin hydrochloride, which is a derivative of metformin present in Riomet (brand name analogs Apo-Metformin, Fortamet, Gen-Metformin, Glucophage, Glucophage XR, Glycon, Metformin HCL, Novo-Metformin, Nu-Metformin). Brand names of combination products include Actoplus Met (Metformin and pioglitazone), Avandamet (Metformin and rosiglitazone), Glucovance (Metformin and Glyburide), Janumet (Metformin and sitagliptin), Kombiglyze (Metformin and saxagliptin), Metaglip (Metformin and Glipizide), PrandiMet

(Metformin and repaglinide), all of which have different clinical implications. Milk Thistle Extract

Milk thistle (Silybum marianum) is comprised of thistle seed flavonoids, including the important Silymarin fractions isosilybinins A and B, silybinins A and B, silychristin and silydianin. This particular group of flavonoids, collectively known as Silymarin is the active ingredient in Milk Thistle Extract. Milk Thistle is also referred to as Artichaut Sauvage, Blessed Milk Thistle, Cardo Lechoso, Cardui Mariae Fructus, Cardui Mariae Herba, Carduus Marianum, Carduus marianus, Chardon Argente, Chardon de Marie, Chardon de Notre-Dame, Chardon Marbre, Chardon- Marie, Epine Blanche, Holy Thistle, Lady's Thistle, Lait de Notre-Dame, Legalon, Marian Thistle,

Mariendistel, Mary Thistle, Our Lady's Thistle, Shui Fei Ji, Silibinin, Silybe de Marie, Silybin, Silybum, Silybum marianum, Silymarin, St. Mary Thistle, and St. Marys Thistle.

Silymarin is known to suppress the proliferation of a variety of tumor cells. This is effected primarily through cell cycle arrest at the Gl/S-phase, induction of cyclin-dependent kinase inhibitors (such as pi 5, p21 and p27), down-regulation of anti-apoptotic gene products (e.g., Bcl-2 and Bcl-xL), inhibition of cell-survival kinases (AKT, PKC and MAPK) and inhibition of inflammatory transcription factors (e.g., NF-kappaB). Silymarin is also known to down-regulate gene products involved in the proliferation of tumor cells (cyclin D 1 , EGFR, COX-2, TGF-beta, IGF-IR), invasion (MMP-9), angiogenesis (VEGF) and metastasis (adhesion molecules). The antiinflammatory effects of silymarin have been shown to be mediated through suppression of NF-kappaB-regulated gene products, including COX-2, LOX, inducible iNOS, TNF and IL- 1.

Silymarin is most readily available in Silymarin supplements and Milk Thistle Extract.

Presently, the most bioavailable milk thistle products are standardized to include 80% silymarin. They are commercially available in supplement form by suppliers suchas Jarrow Formulas Milk Thistle, Vital Nutrients Milk Thistle, and Swanson Superior Herbs Milk Thistle (Standardized). There are some patented solutions of this pharmaceutical grade milk thistle such as Maximum Milk Thistle™ and Ultra Thistle™. Silymarin supplements are also available standardized to 80% (e.g. Metabolic Maintenance, Now Foods).

Milk thistle as an herb is made up of both active and inactive ingredients in varying amounts, with the active ingredients providing all of the supplement's benefits and therapeutic value.

Modified Citrus Pectin

Modified Citrus Pectin (MCP) is a natural pectin powder modified to have a lower molecular weight than regular pectin fiber. Pectin is a soluble fiber found in the rinds and peels of fruits such as oranges, lemons, grapefruits and apples, and is also used as a thickening agent in certain foods, including jellies. Modified Citrus Pectin's smaller molecular size allows it to be easily absorbed into the bloodstream. Modified Citrus Pectin is also known as citrus pectin, Pecta-Sol® and MCP.

Modified Citrus Pectin is known to prevent the growth and spread of cancer by binding over- expressed galectin-3 molecules that are known to play a role in promoting angiogenesis, metastatic cancer, diabetes, liver fibrosis, arthritis and cardiovascular disease. In addition, MCP is known to inhibit cell proliferation by reducing MAP kinase signaling and promoting apoptosis in Prostate Cancer. Another benefit of MCP is its ability to chelate heavy metals and toxins and help eliminate them from the body.

The more preferred forms of Modified Citrus Pectin come in powder form such as those produced by EcoNugenics sold under the name Pecta-Sol®. Other supplements, such as Swanson's PectiPure™ Modified Citrus Pectin contain adequate levels of the low molecular weight MCP with 82% galucturonic acid. Pecta-Sol® Chelation Complex™ is less preferred as it contains a reduced amount of MCP with other alginate dilutions.

N-Acetyl Cysteine

The active ingredient N-Acetyl Cysteine (NAC) is derived from the amino acid L-cystein. It is a more stable form of Cysteine that can be taken as a supplement. Cysteine is an essential amino acid required for the production of glutathione, a free radical fighter.

NAC is also referred to as: Acetyl Cysteine, Acetyl Cysteine, Acetylcysteine, Acetylcysteine, Chlorhydrate de Cysteine, Cysteine, Cysteine, Cysteine Hydrochloride, Cystine, Hydrochlorure de Cysteine, L-Cysteine, L-Cysteine, L-Cysteine HC1, L-Cysteine HC1, NAC, N-Acetil Cisteina, N- Acetyl-B-Cysteine, N-Acetyl Cysteine, N-Acetyl-L-Cysteine, N-Acetyl-L-Cysteine, N- Acetylcysteine, and N-Acetylcysteine.

NAC has been associated with diminished oxidative stress reflected in preserved antioxidant levels and lower inflammation reflected in lower interleukin levels. NAC is also effective to maintain Vitamins C and E in their reduced state, enhancing their effectiveness which in turn makes the produced glutathione more effective. It is also known to prevent apoptosis through inverse regulaton of NFKB and J K pathways and inducing differentiation of the cells. By suppressing the NF-kappa B pathway, it also represents an attractive therapeutic target for treatments to control neutrophilic inflammation. Treatment of certain carcinomas with NAC, monitors expression of the COX-2 protein, inducing apoptosis. It is predicted that this could be effective as a predictor of chemoresistance and that assessment of the COX-2 status could be advantageous to identify cervical cancer patients who may benefit from NAC administration. NAC has also been shown to inhibit both COX-2 expression and NF-kappaB nuclear translocation, which in turn is suggestive that NAC could inhibit the inflammatory process.

NAC is most beneficial (bioavailable) when administered in liposomal form. It is important to use pharmaceutical grade NAC (e.g. Swanson Ultra Pharmaceutical Grade Ajupure® N-Acetyl L- Cysteine).

As an alternative to NAC, some studies suggest that garlic, selenium, alpha-lipoic acid, L- cysteine can also boost cellular levels of Glutathione, although not as effectively. Life Extension produces a supplement that is comprised of Glutathione, Cysteine and Vitamin C. Glutathione molecules are large and have trouble crossing the intestinal system to reach the blood stream, however, there are "Glutathione precursers" that are more easily absorbed. Foods known to be rich in Glutathione include vegetables and fruits such as spinach, broccoli, brussels sprouts, parsley, avocado, asparagus, grapefruit, strawberries, milk thistle, whey protein, etc. In addition there are "Ultimate Antioxidants" that contain NAC and other important antioxidants, but do not reach the quality or bioavailability of these supplements' potential (e.g. Natural Factors® Ultimate Antioxidant contains l OOmg unspecified NAC as well as 13 other ingredients). Milk Thistle, another supplement beneficial to liver health, functions under different mechanisms. (See Milk Thistle supplement above for additional information.)

Naltrexone

Naltrexone hydrochloride is an opioid receptor antagonist that is prescribed as a treatment to reduce the pleasurable effects of alcohol and opiod drugs, thereby reducing cravings. It also has implications in cancer treatment.

Blockage of Opioid Growth Factor (OGF) and OGFr with the nonselective opioid receptor antagonist naltrexone, has been shown to upregulate the expression of OGF and OGFr.

Administration of a low dosage of naltrexone (LDN) has been shown to block endogenous opioids from opioid receptors for a short period of time. The mechanism of action in cancer targets and inhibits tumor cell proliferation and angiogenesis. LDN has a stimulatory effect on immune cells via an indirect interaction with their opiate receptors, whereas high-dose naltrexone has an inhibitory effect.

Naltrexone is the active ingredient found in name brands including Depade, Vivitrol, and Re Via. Naltrexone is most preferably available in pill form in Re Via (formerly called Trexan). Preferably, Vivitrol is administered intramuscularly once a month.

Omega-3 Fatty Acids

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the principal omega-3 fatty acids found in fish oil, derived from the tissues of oily fish. EPA and DHA are known to inhibit cell growth and increase cell death in pancreatic cancer cells via the downregulation of Wnt/Beta- Catenin signaling. In addition, the anti- inflammatory activities of Omega-3 Fatty Acids are effected in part through inactivation of the nuclear factor-kappaB (NF-κΒ) signalling pathway and suppression of the Akt/mTOR signaling pathway.

Omega-3 essential fatty acids produce anti-inflammatory eicosanoids, most notably prostaglandin E2. Resolvins, a class of bioactive lipids, have been shown to inhibit the migration of inflammatory cells to sites of inflammation and are also responsible for turning on other

inflammatory cells. Accordingly, pharmaceutical grade EPA/DHA Omega-3 Fatty Acids help block the Wnt/Beta-Catenin pathway. It has also been shown to reduce oxidative stress up to 20% by reducing free radical formation caused by inflammation. The best source of EPA and DHA come in pharmaceutical grade Omega-3 fish oils commercially available as OmegaBrite®. OmegaBrite® is beneficial for its 90% concentrated pure Omega-3 and 70% pure EPA Omega-3. It has the highest available EPA/DHA ratio of 7: 1.

Alternatively, pharmaceutical grade Omega-3 oils that are effective in the Wnt/Beta-Catenin pathway include Nordic Naturals Omega-3 Purified Fish Oil (EPA/DHA 4: 1), Trilogy Sealogix™ Ultra- Refined Fish Oil (EPA/DHA 2: 1), Block Center's Arctic Essentials, Enzymatic Therapy's, Tyler's Eskimo-3, Jarrow's Max DHA, Renu Premium Pharmaceutical Grade Omega 3 Pure Norwigian Fish Oil (EPA/DHA 2: 1).

Alternative to EPA/DHA Omega-3 fish oil, the following provide EPA and DHA in a less effective manner and may be contaminated by other Omegas (3s, 5s, 6s, 7s, 9s): Pure Krill Oil (e.g.

Swanson's EFAs Krill Oil featuring Superba™ Oil), Cod Liver Oil (e.g. Nordic Naturals Arctic Cod

Liver Oil™), Salmon Oil (e.g. Nordic Naturals Kenai Wild Alasking Salmon Oil), Algae DHA Oil

(e.g. Thorne Research DHA (Omega-3 from Algae)).

Flaxseed Oil (e.g. Swanson EFAs Flaxseed Oil (OmegaTru)), walnuts, soybeans and canola oil are not an alternative because the human body cannot efficiently metabolize the alpha-linolenic acid Omega-3 found in these ingredients. The alpha-linolenic acid cannot be efficiently converted into DHA, and must first be converted to EPA before it can be used.

Pycnogenol extract

Pycnogenol refers to the bioflavonoid product derived from the pine bark of the Pinus maritima tree. Pycnogenol extract represents a variety of compounds that contain proanthocyanidins, the active ingredient in Pycnogenol. It is also referred to as French Maritime Pine Bark Extract, other names for Pycnogenol extract include Condensed Tannins, Ecorce de Pin, Ecorce de Pin Maritime, Extrait d'Ecorce de Pin, French Marine Pine Bark Extract, Leucoanthocyanidins, Maritime Bark Extract, Oligomeres de Procyanidine, Oligomeres Procyanidoliques, Oligomeric

Proanthocyanidins, OPC, OPCs, PCO, PCOs, Pine Bark, Pine Bark Extract, Pinus pinaster, Pinus maritima, Proanthocyanidines Oligomeriques, Procyanidin Oligomers, Procyanodolic Oligomers, Pycnogenol, Pygenol, and Tannins Condenses. These ingredients can also be extracted from other sources, including peanut skin, grape seed, and witch hazel bark.

Pycnogenol is known to suppress TNF-a- induced activation of NFKB, thereby inhibiting inflammation. In addition, ingestion of Pycnogenol extract has been shown to inhibit COX-1 and COX-2 inducible enzyme activity.

Source Natural's Pycnogenol and Grape Seed contains 50mg of French Maritime Pine Bark Extract yielding 90% Proanthocyanidins and organic acids, and 50mg Grape Seed Extract

(Proanthodyn™) has a Procyanidolic value of 95. Source Natural also produces a pure Pycnogenol supplement containing lOOmg 90% Proanthocytanidins. Bluebonnet Pycnogenol contains 95% Pycnogenol from pine bark extract. Similarly Swanson's Ultra Pycnogenol and Twinlab's

Pycnogenol contain the same high dose derived from the French maritime pine tree.

Alternatives include Country Life's Biochem Pycnogenol (l OOmg 85-90%), and Nature's Plus Pycnogenol (50mg 85-90%). It is important to note that many supplements are provided that contain contaminants such as Vitamin C and E, Calcium, fruit extract, and rosemary leaf, decreasing the concentration within each dose. Among these supplements is NOW Foods Pycnogenol.

Quercetin

Quercetin is a flavonoid, or plant-based (phyto)chemical found in the rinds and barks of many plants, including apple skins, onions, tea, red wine, leafy green vegetables, berries, and in herbs such as ginko and St. John's wort.

Quercetin has been shown to inhibit the Sonic Hedgehog pathway, and in conjunction with EGCG was demonstrated to possess synergistic inhibitory effects on self-renewal capacity of CSCs through attenuation of TCF/LEF and Gli activities. Quercetin is also known to be effective as an inhibitor of the NF-κΒ pathway; controlling the protein that plays a pivotal role in the expression of pro-inflammatory cytokines, chemokines, and other growth factors. In a mechanism likely to involve blockage of NF-κΒ activation and upregulation of pro-inflammatory genes, Quercetin induces inhibition of cyclooxygenase-2 (COX-2) expression leading to anti-inflammatory effects including AMP-activated protein kinase (AMPK) anti-proliferatory and pro-apoptotic activity. Quercetin is also known to inhibit cell proliferation and Vascular Endothelial Growth Factor (VEGF) expression in cancer cells in a dose-dependent manner.

The best source for higher dosages of Quercetin is via dietary supplements that are not contaminated with other ingredients like Bromelain or Vitamin C. Commercially available brands include the preferred Life Extension Optimized Quercetin. Other commercially available brands include Swanson's Premium High Potency Quercetin, NOW Foods, Doctor's Best, Jarrow Formulas, TwinLab, Solaray, Source Naturals, Natrol, Natural Factors, NutriCology Allergy Research, and Solgar.

Resveratrol

Resveratrol is a phytoalexin produced by grapevines in response to fungal infection and is found in both the Trans-Resveratrol and Cis-Resveratrol isomer forms. It has been shown to have anti-inflammatory and anticarcinogenic properties. However, only the trans-isomer has been associated with health benefits. Resveratrol is also referred to as 3,4',5-stilbenetriol, 3,5,4' - trihydroxystilbene, 3,4',5-trihydroxystilbene, 3,5,4'-trihydroxy-trans-stilbene, Cis-Resveratrol, Extrait de Vin, Extrait de Vin Rouge, Kojo-Kon, Phytoalexin, Phytoalexine, Phytoestrogen, Phyto- cestrogene, Pilule de Vin, Protykin, Red Wine Extract, Resveratrol, Resveratrols, Resveratrols, RSV, RSVL, Stilbene Phytoalexin, Trans-Resveratrol, Trans-Resveratrol, Wine Extract, and Wine Pill. Trans-Resveratrol is known to possess proapoptotic properties. Trans-Resveratrol has been shown to enhance the effects of vitamin D, a supplement that is converted to a steroid that inhibits the growth of certain cancer cells. Resveratrol has also been shown to make cancer cells (colon, neuroblastoma, esophageal, breast, prostate, certain leukemia, skin, pancreatic, ovarian, melanoma, liver, lung, stomach, oral, cervical, various lymphoma and thyroid) more susceptible to

chemotherapeutic drugs including Gemcetabine, cisplatinum, and Paclitaxel.

The primary source of Trans-Resveratrol is red wine. Resveratrol, although being a grape- derived dietary supplement found in the skin of grapes (also found in peanuts, mulberries, red wine extracts and polyugonum csupidatum), acts differently as it is an antioxidant. The purity of Trans- Resveratrol varies from 50%-99%. A supplement that is 99% Trans-Resveratrol is more pure and bioavailable than the 50% supplement which is most often diluted with Cis-Resveratrol and Emodin. Higher concentrations of Resveratrol are preferred as Trans-Resveratrol has low bioavailability due to the rapid high rate of metabolism.

Many supplements of Grape Seed extract will also contain Resveratrol in addition to the primary supplement (e.g., Life Extension Grapeseed Extract with Resveratrol & Pterostilbene) which have good bioavailability, but act differently than Trans-Resveratrol alone.

Resveratrol is not a substitute for Curcumin.

Rhodiola

Rhodiola (Roseroot) is a plant that, as a flavonoid, is known to possess antioxidant properties. Rhodiola is also referred to as Arctic Root, Extrait de Rhodiole, Golden Root,

Hongjingtian, King's Crown, Lignum Rhodium, Orpin Rose, Racine d'Or, Racine Doree, Racine de Rhadiola, Rhodiola rosea, Rhodiole, Rhodiole Rougeatre, Rodia Riza, Rose Root, Rose Root Extract, Rosenroot, Roseroot, Rosewort, Sedum rhodiola, Sedum rosea, Siberian Golden Root, Siberian Rhodiola Rosea, and Snowdown Rose.

The root extracts of rhodiola have been shown to possess strong anti-depressant activity and anticancer effects. Rhodiola is thought to help the body adapt to stressors by preventing release of catecholamine and increase in cyclic AMP levels in the myocardium, and by depleting adrenal catecholamine. Salidroside, a phenylpropanoid glycoside isolated from Rhodiola rosea L, has been shown to have a protective effect against hypoxia-induced cardiomyocytes necrosis and apoptosis by increasing HIF- 1 alpha expression and thereby up-regulating VEGF levels.

Rosemary

The three active ingredients in Rosemary (Rosmarinus officinalis L.) are carnosol (CS), carnosic acid (CA) and rosmarinic acid (RA). Rosemary is also referred to as Compass Plant, Compass Weed, Encensier, Herbe Aux Couronnes, Old Man, Polar Plant, Romarin, Romarin Des Troubadours, Romero, Rose de Marie, Rose Des Marins, Rosee De Mer, Rosemarine, Rosmarinus officinalis, Rusmari, and Rusmary. Rosemary extract (Rosemaria), a product derived from rosemary, has been shown to inhibit the proliferation of ovarian cancer cell lines. It has also been shown to induce apoptosis by modifying the expression of multiple genes. Studies have provided evidence that carnosol targets multiple deregulated pathways associated with inflammation and cancer that include nuclear factor kappa B (NFKB), apoptotic related proteins, phosphatidylinositol-3 -kinase (PI3 K)/Akt, ERK signaling pathways, androgen and estrogen receptors, as well as molecular targets. In addition, carnosol appears to be well tolerated in that it has a selective toxicity towards cancer cells versus non-tumorigenic cells and studies have shown that it is well tolerated when administered to animals.

The preferred source of carnosol is rosmarinic acid extract (e.g. Life Extension). Swanson provides a supplement with 6% standardized rosmarinic acid. Less preferred supplements are comprised of Rosemary before it is extracted to increase the concentration of rosmarinic acid.

Selenium

The active ingredient in the mineral Selenium is Selenium sulfide. Selenium is also referred to as Atomic number 34, Dioxyde de selenium, Ebselen, L- Selenomethionine, L- Selenomethionine, Levure selenisee, Numero atomique 34, Se, Selenio, Selenite, Selenite de sodium, Selenium,

Selenium Ascorbate, Selenium Dioxide, Selenized Yeast, Selenomethionine, Selenomethionine, and Sodium Selenite.

Selenium has been shown to have potential as an effective agent to improve the therapeutic effect of chemotherapy as it is negatively correlated with VEGF. In addition, Selenium may, in the case of prostate cancer, protect the prostate from prostatitis-induced cancer by inhibiting nuclear translocation of the NF-(K)B and the subsequent production of the immunosuppressive cytokine TGFbeta(l), proangiogenic factor VEGF, and pro-inflammatory factor IL-6. Selenium is also known to down-regulate the transcription of COX-2 and other pro-inflammatory genes.

The best source for Selenium and Sodium Selenite are pure supplemental forms without yeast contamination. Life Extension's Sodium Selenite or Swanson Selenium are viable options. Swanson also produces Swanson Albion Complexed Selenium that contains Albion Complexed Selenium and a blend of ginger root, Piper longum and Piper nigrum for enhanced absorption.

There are also commercially available products whose brand names include Se Aspartate and Selepen. The best sources of selenium naturally are whole grains, tomatoes and other vegetables, seafood (crab, fish), nuts (particularly Brazil nuts), garlic, and onions; meat and poultry (liver) also provide significant amounts. Interactions with zinc might make it more difficult for the body to absorb selenium from food.

Sulforaphane

Sulforaphane is a chemical found in certain vegetables such as broccoli, cabbage, and cauliflower. Sulforaphane is also referred to as SFN, Sulforafane, Sulforaphane Glucosinolate,

Sulforofano, Sulphoraphane, l -isothiocayanate-4-methyl-sulfonyl butane. Sulforaphane has been shown to target pathways of apoptosis, cell cycle arrest, and oxidative stress in human pancreatic cancer cells. It has been shown to suppress TNF-alpha activation of NF- kappaB and induce apoptosis. Inhibition of HIF- 1 alpha by sulforaphane results in decreased expression of VEGF.

Tetrathiomolybdate

Tetrathiomolybdate (TM) is a copper chelating compound. Angiogenesis (new blood vessel growth) is required for tumor growth, and a sufficient level of copper is required for angiogenesis. It has been established that there is a range within which the copper level can be reduced that inhibits angiogenesis in tumors but does not interfere with vital cellular functions of copper.

Suppression of NF-κΒ is the major mechanism by which TM is effective to inhibit angiogenesis and metastasis. NF-κΒ has been shown to regulate genes important for angiogenesis, invasion, and metastasis. Inhibiting NF-κΒ activity has been shown to suppress VEGF and IL-8 expression, resulting in a decrease in tumor angiogenesis in various carcinoma cells (breast, prostate). Administration of TM also significantly decreases tumor cell motility and invasiveness by inhibiting lysyl oxidase (LOX) activity, FAK activation, and MMP2 levels. Furthermore, TM activates p38 MAPK cell death pathway and by downregulating XIAP enhances survival protein expression.

Tetrathiomolybdate is only available by prescription from a compounding pharmacist as it has a very short shelf-life. In order to stay within the ideal concentration range, a larger dose is required initially until copper chelated out of blood has a targeted ceruloplasmin score of 10- 15. Subsequently, the dose can be reduced to a maintenance level of TM.

Tetrathiomolybdate has the molecular structure M0S₄ and is a dianion. There are several salt complexes that can be used in the scope of this invention. Common complexes are ammonium tetrathiomolybdate, (NH₄)₂MoS₄, tetraalkylammonium tetrathiomolybdate, such as those described in U.S. Pat. Nos. 6,703,050, 6,855,340, 6,951 ,890, 7, 189,865, 7,416,741 , and 7,888,389. Specifically tetrapropylammonium tetrathiomolybdate and choline tetrathiomolybdate (also called ATN-224) are preferred.

Alternative copper lowering agents can be substituted for TM, such as d-penicillamine, trientine hydrochloride, and those described in US patent 7,851 ,505.

Vitamin C

The active ingredient in Vitamin C is ascorbic acid. Vitamin C is also referred to as Acide

Ascorbique, Acide Cevitamique, Acide Iso-Ascorbique, Acide L-Ascorbique, Acido Ascorbico, Antiscorbutic Vitamin, Ascorbate, Ascorbate de Calcium, Ascorbate de Sodium, Ascorbyl Palmitate, Calcium Ascorbate, Cevitamic Acid, Iso-Ascorbic Acid, L-Ascorbic Acid, Magnesium Ascorbate, Palmitate dAscorbyl, Selenium Ascorbate, Sodium Ascorbate, Vitamina C, Vitamine

Antiscorbutique, and Vitamine C. Vitamin C is known to down-regulate VEGF and VEGFR-2 expression through oxidative stress reduction, which involves the HIF- 1 alpha signaling pathway. In addition Vitamin C is known to play a role in inhibition of COX-2 expression, and Vitamin C also suppresses TNF alpha-induced NFkappaB activation by inhibiting IkappaBalpha phosphorylation.

Other sources of Vitamin C include fruits and vegetables, especially citrus.

Vitamin D3

The active ingredient in Vitamin D3 is Cholecalciferol. Common derivatives are calcitriol (l ,25-dihydroxyvitamin D3) and tacalcitol (l ,24(R)-dihydroxyvitamin D3).

Vitamin D3 is known to induce anti-apoptotic PI3/AKT signaling and increase VEGF expression and release in vascular smooth muscle cells. The expression of cyclooxygenase-2 (COX- 2) gene is significantly decreased by calcitriol. Calcitriol actually inhibits the prostaglandin (PG) pathway by three actions: (i) the inhibition of the expression of cyclooxygenase-2 (COX-2), the enzyme that synthesizes PGs, (ii) the induction of the expression of 15-prostaglandin dehydrogenase (15-PGDH), the enzyme that inactivates PGs and (iii) decreasing the expression of EP and FP PG receptors that are essential for PG signaling. Calcitriol and tacalcitol, derivatives of Vitamin D3, are known to inhibit the synthesis of pro-inflammatory cytokines IL-6 and IL-8.

A fraction of Vitamin D, namely Vitamin D3 and its derivatives, are more effective than Vitamin D. They are commercially available in 'high potency' forms through several suppliers. Swanson Premium and Life Extension provide High Potency Dry Vitamin D3. Carlson, Weil Nutritional Supplements, Metagenics, and many others produce the vitamin in acceptable forms.

Synthetic vitamin D analogs (deltanoids) are currently under development. Examples are KH- 1060, EB- 1089, l alpha-hydroxyvitamin D5, vitamin D2, and QW- 1624F2-2.

Vitamin E

The active ingredient in Vitamin E is alpha-tocopherol. Vitamin E exists naturally in eight chemical forms (alpha-, beta-, gamma-, and delta-tocopherol and alpha-, beta-, gamma-, and delta- tocotrienol), and Alpha- (or a-) tocopherol is the only form that is bioavailable for human consumption.

Vitamin E is also referred to as Acetate d'Alpha Tocopherol, Acetate d'Alpha Tocopheryl, Acetate de D-Alpha-Tocopheryl, Acetate de DL-Alpha-Tocopheryl, Acetate de Tocopherol, Acetate de Tocopheryl, Acetate de Vitamine E, All Rac-Alpha-Tocopherol, All-Rac-Alpha-Tocopherol,

Alpha-Tocopherol, Alpha Tocopherol Acetate, Alpha Tocopheryl Acetate, Alpha tocotrienol, Alpha tocotrienol, Alpha-tocopherol, Alpha-Tocopherol, Beta tocotrienol, Beta-tocotrienol, Beta- tocopherol, Beta-tocopherol, Concentre de Tocotrienol, D-Alpha Tocopherol, D-Alpha Tocopherol, D-Alpha Tocopheryl Succinate, D-Alpha Tocopheryl Acetate, D-Alpha Tocotrienol, D-Alpha Tocotrienol, D-Alpha-Tocopherol, D-Alpha-Tocopherol, D-Alpha-Tocopheryl Acetate, D-Alpha- Tocopheryl Acid Succinate, D-Alpha-Tocopheryl Succinate, D-Alpha-Tocopheryl, D-Alpha- Tocopheryl, D-Beta-Tocopherol, D-Beta-Tocopherol, D-Delta-Tocopherol, D-Delta-Tocopherol, Delta Tocotrienol, Delta-Tocotrienol, Delta-tocopherol, Delta-tocopherol, D-Gamma Tocotrienol, D- Gamma-Tocotrienol, D-Gamma-Tocopherol, D-Gamma-Tocopherol, DL-Alpha-Tocopherol, DL- Alpha-Tocopherol, DL-Alpha-Tocopheryl Acetate, DL-Alpha-Tocopheryl, DL-Alpha-Tocopheryl, DL-Tocopherol, DL-Tocopherol, D-Tocopherol, D-Tocopherol, D-Tocopheryl Acetate, Fat-Soluble Vitamin, Gamma tocotrienol, Gamma-tocotrienol, Gamma-tocopherol, Gamma-tocopherol, Mixed Tocopherols, Mixed Tocotrienols, Palm Tocotrienols, Rice Tocotrienols, RRR-Alpha-Tocopherol, RRR-Alpha-Tocopherol, Succinate Acide de D-Alpha-Tocopheryl, Succinate Acide de Tocopheryl, Succinate de D-Alpha-Tocopheryl, Succinate de Tocopheryl, Succinate de Vitamine E, Tocopherol Acetate, Tocopherol, Tocopherol, Tocopherols Mixtes, Tocotrienols de Palme, Tocotrienols de Riz, Tocotrienols Mixtes, Tocopheryl Acetate, Tocopheryl Acid Succinate, Tocopheryl Succinate, Tocotrienol, Tocotrienol, Tocotrienol Concentrate, Tocotrienols, Tocotrienols, Vitamin E Acetate, Vitamin E Succinate, Vitamina E, Vitamine E, Vitamine Liposoluble, and Vitamine Soluble dans les Graisses.

Vitamin E is known to down-regulate VEGF and VEGFR-2 expression through oxidative stress reduction which involves the HIF- 1 alpha signaling pathway. In addition Vitamin E is known to play a role in the inhibition of COX-2 expression in macrophages.

WOBENZYM® N enzyme blend

Wobenzym® N is a systemic enzyme product indicated for pancreatic enzyme deficiency. The enzyme blend in Wobenzym® N contains the following, clinically studied enzymes: pancreatin (protease (pancreas) Sus scrofa), papain (Carica papaya), bromelain (Ananas comosus), trypsin ((pancreas) Sus scrofa), and chymotrypsin ((pancreas) Bos taunts) in addition to Rutoside trihydrate ((Rutin) Sophara japonica). Each one of these is a protease, which simply means that they break down proteins.

The composition and equivalence of Wobenzym® N is similar to Medizym which contains the same ingredients in different doses. Brand name alternatives include Pancrease®,

Pancrease®MT, Creon®, Protilase®, Pangestyme®, Panokase®, Lipram®, Ultrase®, Viokase®, Zenpep® and Zymase® and non-brand name Lipancreatin.

Pancreatic enzyme supplements include those that combine the primary digestive enzymes (protease for protein digestion, amylase for carbohydrate digestion, and lipase for fat digestion) into one supplement as an alternative to Pancreatin. Life Extension Enhanced Super Digestive Enzymes is an example of this combined supplement which also includes other vegetarian enzymes and papaya. Vital Nutrients combines only the three enzymes in its Vital Nutrients Pancreatic Enzymes blend. Garden of Life Ω-Zyme™ combines 20 different vegetarian digestive enzymes.

Zinc Zinc is known as an essential trace element metal. Zinc is also referred to as Acetate de Zinc, Acexamate de Zinc, Aspartate de Zinc, Atomic Number 30, Chlorure de Zinc, Citrate de Zinc, Gluconate de Zinc, Methionine de Zinc, Monomethionine de Zinc, Numero Atomique 30, Orotate de Zinc, Oxyde de Zinc, Picolinate de Zinc, Pyrithione de Zinc, Sulfate de Zinc, Zinc Acetate, Zinc Acexamate, Zinc Aspartate, Zinc Chloride, Zinc Citrate, Zinc Difumarate Hydrate, Zinc Gluconate, Zinc Methionine, Zinc Monomethionine, Zinc Murakab, Zinc Orotate, Zinc Oxide, Zinc Picolinate, Zinc Pyrithione, Zinc Sulfate, Zinc Sulphate, Zincum Aceticum, Zincum Gluconicum, Zincum Metallicum, Zincum Valerianicum, and Zn.

Zinc has been shown to influence both apoptosis and protein kinase C activity.

Brand names include Orazinc and Galzin. Several foods provide a good source of zinc, most notably, oysters, but also red meat and poultry, beans, nuts, seafood (especially crab and lobster), whole grains, and dairy products. Phytates, present in whole-grain breads and legumes, bind zinc and inhibit its absorption, lowering its bioavailability. Pharmaceutical supplements contain several different forms of zinc, including zinc gluconate, zinc sulfate, and zinc acetate.

There are indications that Zinc interacts with the following supplements: Calcium, Phytic acid, Iron, decrease dietary zinc absorption. Large amounts of zinc can reduce copper absorption and disrupt magnesium balance. Riboflavin (Vitamin B2) can increase zinc absorption, as well as Vitamin D. EDTA is a chemical compound that removes excess metals, especially lead, and works by binding with (chelating) the metal. Repeated high doses of EDTA, can reduce blood zinc levels.

The following Tables 1 -6 provide a list of nutraceutical compounds and/or non- chemotherapeutic drugs for use in the methods and compositions of the present invention, in particular for the treatment of pancreatic cancer. Each table lists compounds useful for particular categories of cancer-affected metabolic pathways, intercellular signaling pathways, or intracellular signaling pathways, and thus a composition of the invention will be comprised of a combination of compounds selected from at least the first four tables (Tables 1 -4), and for the treatment of pancreatic cancer, the compositions of the invention will be comprised of a combination of compounds selected from all six tables (Tables 1 -6). By conducting a careful analysis of, for example, a blood sample from a patient suffering from pancreatic cancer, a compound or compounds will be chosen from each table (depending on the results of the blood test) to create a nutraceutical/non-chemotherapeutic drug "cocktail" to administer to the patient. By following the teachings disclosed herein, one skilled in the art, for example a patient's oncologist or primary care physician, will be able to choose the most beneficial combination of compounds as well as the optimal dosage of each. As some compounds are listed in more than one table below, it will be understood by one skilled in the art that if, for example, curcumin is chosen from Table 1 , it will not be chosen from any other table in which it is listed for preparation of a composition according to the present invention. Table 1

Curcumin Omega 3 fish oil

Resveratrol Green Tea Extract - EGCG

Baicalein Genistein

Rhodiola Rosemaria

Sulforaphane

A particularly preferred combination or supplement for the treatment of patients diagnosed with pancreatic cancer, along with a preferred dosage regimen is set forth in Table 1 1 :

Metformin 500mg 1 500mg

Tetrathiomolybdate 30mg 4 120mg

Alpha Lipoic Acid 300mg 4 1200mg

Acetyl- 1 -carnitine 500mg 2 lOOOmg

Milk Thistle Extract (Silymarin) 500mg 1 500mg

Vitamin C 500mg 4 2000mg

Vitamin E 400IU 3 1200 IU

Fucoidan 300mg 1 300mg

Gravida 750mg 4 3000mg

Active Pectin 500gm 2 lOOOg

Rhodiola lOOmg 1 lOOmg

Pvosemaria 250mg 2 500mg

Natural Signaling Pathway Inhibitors

Described below is a collection of nutraceutical products that were prescribed to the patient with pancreatic cancer reported in Example 1. As described above, the exact makeup of a pharmaceutical composition according to the invention and dosages of the component compounds can be determined by the attending physician, e.g., oncologist or primary care physician, taking into account the physical characteristics of the patient and the results of biopsies, blood analyses, and other tests. The signaling pathways which each compound is known to affect are listed in parenthesis:

1) CURCUMIN (HEDGEHOG, EGFR, VEGF, COX-2, NFkB, PI3K/AKT/mTOR, Bcl-2 ), IGF- 1, p53);

2) GENISTEIN (Soy Isoflavone) (HEDGEHOG, MAPK, PI3K/AKT, EGFR, NFkB, SURVIVIN [IAP], p53, p21);

3) EGCG (Green Tea Extract) (HEDGEHOG, EGFR, COX-2, VEGF, PI3K/AKT, MAPK, p53, Bcl-2; XIAP FAK, IGF-1);

4) RESVERATROL (HEDGEHOG, EGFR, VEGF, NFkB, IGF- 1, p53, SURVIVIN [IAP]);

5) APIGENIN (Flavonoid) (HEDGEHOG, NFkB, PI3K/AKT, MAPK, VEGF) ;

6) BAICALEIN (Scutellaria Baicalensis. Chinese herb) (HEDGEHOG, COX-2, NFkB, EGFR, ERK 1/ 2, XIAP,p53); 7) OUERCETIN (Flavonoid) (HEDGEHOG, COX-2, VEGF, SURVIVIN,PI3K/AKT/mTOR;

MAPK; IGF- 1 , FAK);

8) VITAMIN D3 (HEDGEHOG, EGFR);

9) OMEGA-3 FATTY ACIDS (e.g.. fish oil) (VEGF, COX-2, MAPK, LOX, NFkB, p53, p21 , BCL- 2);

10) LICORICE (GLYZZHERIZIN) (EGFR);

1 1) PYCNOGENOL (EGFR, COX-2) ;

12) BOSWELLIA (VEGF, LOX, 5-HETE, COX-2);

13) GRAPE SEED EXTRACT (VEGF, COX-2, EGFR); and

14) SELENIUM (VEGF).

The above list of natural compounds, which includes just one vitamin (D3) and one mineral (selenium), were selected based on a large body of scientific literature indicating that they block or inhibit the signaling pathways mentioned in parentheses after each compound. In a few cases, it should be noted that these compounds not only abrogate cancer-supportive and angiogenic pathways, they also activate or stimulate anti-tumor or anti-angiogenic pathways. Thus, the object of the treatments described herein is not exclusively focused on blocking direct oncogenic processes; rather, the object is ultimately to address directly oncogenic and indirectly oncogenic pathways, and to restore anti-oncogenic processes, to the end of eliminating tumor cells and to making it impossible for growing tumors to thrive in their local environments. Preferred compositions and methods promote the activation, re-activation, or repair of the two most conspicuous tumor suppressor genes: p53 and p21. Most of the compounds listed above have been shown capable of "turning on" p53 which had been switched off, allowing tumors to escape apoptosis (programmed cell death); or by correcting the actions of a mutant p53 so it becomes active again as a tumor suppressor.

Most of the compounds are selected for their ability to interrupt oncogenic and angiogenic tumor cell signaling. However, it is important to note that the evidence favoring the use of these compounds is far more grounded scientifically than just the evidence that they interfere with one or a multiplicity of different pathways. Most of these compounds have been shown - either in the same studies of signal abrogation or in different studies— to actually kill cancer cells by switching on apoptosis, one of the goals of the present methods and compositions described herein. Indeed, they have not only been shown to be effective in vitro killers of cancer cells or in vivo killers of animal tumors or in vivo inhibitors of tumor angiogenesis in animals, but they have been shown to possess all of these capacities specifically against pancreatic cancer.

Every natural compound on the list, with the exception of Vitamin D3, selenium,

Pycnogenol, and Boswellia have been shown to directly induce apoptosis in pancreatic

adenocarcinoma cells in vitro. See, Subramaniam et al., PLoS One, 1 1 :6(2):el 6958 (201 1); Buchler, et al., Pancreas, 26(3):264-73 (2003); Qanungo, et al., Carcinogenesis,.26(5):958-67 (2005); Ding, et al., Pancreas, 25(4):e71-6 (2002); Melstrom, et al., Pancreas, 37(4):426-31 (2008); Ding, et al., Biochem Biophys Res Commun., 266(2):392-9 (1999); Borska, et al., Folia Histochem Cytobiol, 48(2):222-9 (2010); Dekoi, et al., J Surg Res., 139(1): 106-12. (2007); Jutooru, et al., Mol Carcinog, 48(8):692-702 (2009); Sun, et al., Adv Exp Med Biol, 614: 179-86 (2008). Many have demonstrated this capacity against a wide range of different established pancreatic cancer lines, often in multiple replications of the original research. Likewise, at least half of these compounds have also been shown to suppress tumor angiogenesis in pancreatic cancer models. See, Subramaniam, et al., PLoS One, l l :6(2):el6958 (2011); Buchler, et al, Cancer, 100(1):201-10 (2004); Shankar, et al, Front Bioscl , 13 :440-52 (2008); Harikumar, et al, Int J Cancer, 127(2):257-68 (2010);

Zhou, et al, Nt J Oncol, 37(3):551-61 (2010). For example, recent research at the University of Texas Health Sciences Center, which encompassed both in vitro and in vivo studies of pancreatic tumor xenografts in mice, treated these mice with EGCG, the key catechin in Green Tea (see, Shankar, et al. (2008), op. cit.) The researchers found that AsPC-1 (a pancreatic cancer cell line) xenografted tumors treated with EGCG showed significant reduction in volume, proliferation (Ki-67 and PCNA staining), angiogenesis (vWF, VEGF and CD31) and metastasis (MMP-2, MMP-7, MMP-9 and MMP-12) and induction in apoptosis (TUNEL), caspase-3 activity and growth arrest (p21/WAFl). These researchers had used multiple biomarkers to come to the strong conclusion that overall, their data suggest that EGCG inhibits pancreatic cancer growth, invasion, metastasis and angiogenesis, and thus could be used for the management of pancreatic cancer prevention and treatment.

Furthermore, it is now believed that cancer stem cells most likely represent the sub- population of pancreatic cancer cells (and for other solid tumors) that is resistant to cytotoxic cancer therapies, and hence the cause of persistent recurrences. The same compound mentioned above, Quercetin, was recently shown in research from Germany to target pancreatic cancer stem cells. The research included both in vitro and in vivo studies, concluding from the in vivo studies that Quercetin inhibited growth of cancer stem cell-enriched xenografts associated with reduced proliferation, angiogenesis, cancer stem cell-marker expression and induction of apoptosis. Zhou, et al., Nt J Oncol , 37(3):551-61 (2010). Quercetin is not, however, the only compound to inhibit pancreatic cancer angiogenesis or cancer stem cell growth. While the stem cell finding is unusual, most of the compounds above also inhibit pancreatic tumor angiogenesis.

Strikingly, many of the compounds above have specifically been shown to overcome the resistance to chemotherapies exhibited by pancreatic cancer. For example, Curcumin helps overcome resistance to GEMCITABINE, at least partly via suppression of NF-KappaB, a well- established mechanism of chemoresistance to GEMCITABINE. Kunnumakkara, et al., Cancer Res., 67(8):3853-61 (2007); Lev-Ari, et al., Cancer Invest. , 25(6):41 1-8 (2007). Genistein has been shown in multiple studies to help overcome resistance of pancreatic cancer cells and tumors to Platinum- based chemotherapies. Baneriee, et al., Int J Cancer, 128(5): 1240-50 (201 1); Mohammad, et al., Cancer, 106(6): 1260-8 (2006). In studies at the Robert H. Lurie Comprehensive Cancer Center in Chicago, Apigenin was shown to counteract pancreatic cancer cell resistance to Gemcitabine.

Apigenin specifically restored sensitivity of a chemoresistant pancreatic cancer cell line, AsPC- 1 , to the cytotoxic effects of Gemcitabine, causing significant cell growth inhibition and apoptosis in a dose-dependent manner. Strouch, et al., Pancreas, 38(4):409- 15 (2009). In research published in 2010, a team of researchers at M.D. Anderson Cancer Center in Houston, TX, led by Bharat B. Aggarwal, M.D., Professor of Experimental Therapeutics and a world leader of research on natural compounds for cancer, found that Resveratrol potentiated the responses of pancreatic cancer cell lines to the cytotoxic effects of Gemcitabine (see, Harikumar, et al., Int J Cancer, 127(2):257-68 (2010)). Dr. Aggarwal and colleagues noted that Resveratrol inhibited the proliferation of 4 different human PaCa cell lines, synergized the apoptotic effects of gemcitabine, inhibited the constitutive activation of NF-kappaB and expression of bcl-2, bcl-xL, COX-2, cyclin D l MMP-9 and VEGF. In an orthotopic model of human PaCa, they also found that resveratrol significantly suppressed the growth of the tumor (p < 0.001) and this effect was further enhanced by gemcitabine (p < 0.001).

The voluminous research on the compounds listed above is notable not just for the establishment of the depth and breadth of the signaling pathways they disrupt, but for the coincident research demonstrating that most of these same compounds cause the death (apoptosis) of pancreatic cancer cells, inhibit the growth of pancreatic tumors in animal models, and reduce the resistance of pancreatic cancer cells and tumors to standard chemotherapy drugs - agents to which these cells and tumors are, normally, without bio-modulation, sorrowfully ineffective.

Non-Chemotherapeutic Drugs

A series of non-chemotherapeutic drugs were chosen as significant components of the methods and compositions described herein, based on research demonstrating their capacity to suppress or disrupt key signaling pathways involved in pancreatic cancer. The evidence supporting their anti-cancer efficacy varies from agent to agent, but in almost all cases there is sound published evidence of anti-cancer activity, and in some cases anti- angiogenic activity.

Non-chemotherapeutic drugs that will be useful in the practice of this invention include, but are not limited to:

1) METFORMIN - Low doses of the most commonly used diabetes drug has shown multiple pathway effects against cancer. Among its most important potential roles in cancer therapy is its capacity to improve insulin sensitivity, which results in a reduction in insulin levels and a marked reduction in the quantity and activity of Insulin Growth Factor- 1 (IGF- 1), which is a critical driver of malignant growth in pancreatic cancer. Bao, et al., Biochem Biophys Acta. , Epub (2010). Researchers from UCLA have identified cross-talk between insulin/IGF- 1 and GPCR signaling systems as a key to pancreatic cancer growth, and since Metformin has been shown to block this cross-talk, they propose Metformin as a promising candidate for pancreatic cancer prevention and treatment.

Pvozengurt, et al., Clin Cancer Res., 16(9):2505- 1 1 (2010). There is also evidence that Metformin assists in a shift form aerobic glycolysis (the "Warburg Effect") to glucose oxidation, which results in restoration of normal mitochondrial function that, in turn, triggers a renewed capacity for undergoing apoptosis. Martinez-Outschoorn, et al., Cell Cycle, 9(16):3256-76 (2010).

The dosage regimen will be designed by the attending physician to address the particular metabolic pathways implicated in the disease, for the particular patient, bearing in mind, of course, that in selecting the appropriate dosage in any specific case, consideration must be given to the patient's weight, general health, age, and other factors which may influence response to the drug. In general, in a composition according to the invention for treating pancreatic cancer, the dosage range will be 50 - 2000 mg/day, preferably 500 - 1000 mg/day. Alternatively, doses of l OOmg, 250mg, 500mg, 625mg, 750mg, 850mg, or l OOOmg from one to four times a day, or similar dosing regimens, may be administered.

2) TETRATHIOMOLYBDATE ("TM") - TM is currently used to treat Wilson's Disease as a copper chelator. It reduces serum copper, a major co-factor in the processes that undergird tumor angiogenesis. Studies and early trials, mostly from the University of Michigan but also, most recently, from New York- Presbyterian Weill Cornell Medical Center, led by breast cancer oncologist Linda Vahdat, have shown that tumor angiogenesis is effectively suppressed in those patients who achieve low threshold targets for reduced copper levels. Pass, et al., Ann Thorac Surg. , 86(2):383-9 (2008); Brewer, et al., Clin Cancer Res. , 6(1): 1 - 10 (2000); Jain, et al., ASCO 2010 meeting.

Abstract No. 297.

With respect to the dosing and monitoring of a treatment regimen that includesTM, the following guidelines should be followed:

Monitoring for correct dosing of TM is accomplished by two standard blood tests. The first is the ceruloplasmin (cp) test which is a surrogate measurement for copper and the only reliable measurement. Before commencing TM dosing the patient has: (1) a ceruloplasmin test and (2) a zinc serum blood test. These tests provide a baseline and provide the physician with the relevant measurements to appropriately prescribe dosing of TM to match the patient's specific chemistry. The cp test should be administered every two weeks. Once cp levels approach the desired range at about 13- 16, cp tests should be performed every 10 days. Concomitantly TM dosage should be titered to achieve the optimal dosage to maintain cp ideally between 8- 10 cp. Zinc serum

measurements may be done from time to time with a goal of achieving zinc levels that are approximately three time cp levels. Suitable amounts of TM commence with dosing 30mg - 240 mg per day. A typical contemplated regimen would be eight 30mg pills per day: two with each of three meals/day and two pills at bedtime.

When ceruloplasmin (cp) is measured between 16-20 cp, the dosage may be reduced to one 30mg pill four times daily. When cp levels reach 13- 16 cp, the dosage may be reduced to five 20mg pills per day, administered as follows: Two 20mg pills at breakfast, one at lunch, one at dinner, one at bedtime. The desired cp level is 8- 12. Titer TM dosing to achieve cp levels between 8- 12, preferably 8- 10. Patent cp levels below 7 result in a feeling of fatigue.

3) NALTREXONE (Low-Dose^") - It has been demonstrated that low-doses of the opioid antagonist Naltrexone, given before bedtime, is associated with clinical improvement and some remissions, even among patients on no conventional cancer therapies. Bihari, B., 2009, Low-Dose Naltrexone for Cancer, online publication at: www.lowdosenaltrexone.org/ldn_and_cancer.htm. A series of published cases in the journal Integrative Cancer Therapies documented the complete remissions of 4 patients with advanced pancreatic cancer who combined intravenous high doses of the antioxidant Alpha-Lipoic Acid along with daily low-dose oral Naltrexone. Berkson and Berkson, Integr. Cancer Ther. , 5(l):83-9 (2006); Berkson, et al., Integr. Cancer Ther. 8(4):416-22 (2009), erratum in Integr. Cancer Ther., 9(2):247 (2010).

Suitable amounts of Naltrexone will be 0.1 - lOmg, preferably 1.0 - l Omg, more preferably 1.5 - 4.5mg. For the purposes herein, preferred doses are 3.0mg and 4.5mg. Related compounds such as (S)-N-methylnaltrexone and Nalmefene may also be used in place of Naltrexone, at equivalent Naltrexone dose.

Specific mention is made of a composition comprising the above-described three non- chemotherapeutic drugs. These three in combination, i.e., Metformin, Tetrathiomolybdate, and Naltrexone, provide a novel composition for treatment of pancreatic cancer that addresses critical processes in cancer development and thus provides a useful composition for the therapeutic approach to treatment taught herein. The use of these three drugs in combination for cancer treatment, especially as an adjunct to chemotherapy, is a novel combination providing effects on several of the most important metabolic, intercellular signaling, and intracellular signaling pathways that are dysregulated in pancreatic cancer and other cancers. These include, notably, the pro-angiogenic processes, tumor suppression, and Warburg effect/anaerobic glycolysis/oxidative stress.

Accordingly, compositions comprising Metformin, Tetrathomolybdate, and Naltrexone, are a particularly promising embodiment of the present invention.

4) CELEBREX (CELECOXIB) - The selective COX-2 inhibitor has been included in scores of clinical trials of various cancers, mostly as an adjunct to chemotherapy but occasionally as a single agent. While there is still no well-designed randomized trial that has proven its benefits, the fact that Celebrex shrinks premalignant colon polyps (mostly FAP); that it has the demonstrated capacity to shrink mammary tumors in mice; and that its target - the COX-2 enzyme - is a pivotal regulator of the inflammatory cascade and is overexpressed in many solid tumors (including those of most pancreatic cancer patients) bolsters its real potential as an adjunctive cancer treatment (see, Koki and Masferrer, Cancer Control, 9(2 Suppl):28-35 (2002)). An early study of COX-2 in pancreatic cancer demonstrated that levels of COX-2 messenger R A were increased by greater than 60-fold in pancreatic cancer tissue as compared to adjacent non-cancerous tissue. See, Tucker, et al., Cancer Res., 59(5):987-90 (1999)); see, also, Tucker, et al., Carcinogenesis, 25(3):419-23 (2004), and Lipton, et al., J Clin Gastroenterol, 44(4):286-8 (2010).

Although Celebrex has shown direct results in pancreatic cancer, other COX-2 inhibitor compounds may also be used.

5) MELATONIN - This pineal hormone could have been included in either the category of nutraceutical compounds or this category of non-chemotherapeutic drugs, as it sits on the borderline between these categories. Melatonin has known, potent anti-oxidant, anti-inflammatory, and antitumor properties, but it also influences oncogenic pathways including mTOR, which plays a role in pancreatic cancer. Melatonin induces pro-apoptotic signaling in pancreatic cancer cells; restores mitochondrial function which in turn restores apoptosis of pancreatic cancer cells; and enhances patients' responses to Capecitabine (XELODA). Leja-Szpak, et al., J Pineal Res., 49(3):248-55 (2010); Gonzalez, et al., J Pineal Res., Epub 2010; Ruiz-Rabelo, et al., Pancreas, Epub 2010.

Suitable amounts of Melatonin will be 0.3 - 75mg, preferably 1.0 - 50mg, more preferably 1.0 - 20mg, more preferably 1.0 - lOmg, more preferably 2.0 - lOmg per day. Most preferably the dosage amounts will range between 0.3 and 5.0mg, between 1.0 and 5.0mg, or between 3.0 and 6.0mg, with all or part of the dose being administered at night/bedtime. Particularly preferred dosages will be 3.0 - 6.0mg nightly, or 10 - 50mg nightly in severe cases.

The compositions of the present invention are advantageously added to a program of chemotherapy. The compositions of the invention supplement the chemotherapeutic action by addressing additional processes and pathways not addressed by chemotherapeutics and on which the cancer cells of the patient could rely for energy, unchecked proliferation, and migration if such processes and pathways were not controlled or normalized. The effectiveness of any suitable chemotherapeutic used for the treatment of pancreatic cancer will be improved by adding compositions and combination therapies according to the invention. For treatment of pancreatic cancer, typical chemotherapeutics include Gemcitabine and FOLFIRINOX.

FOLFIRINOX has been considered for use as a first line chemotherapy but is also often chosen as a second line chemotherapy. FOLFIRINOX, the combination of Continuous Infusion of 5- FU and Leucovorin with Irinotecan and Oxaliplatin, has been shown to produce significantly longer Progression-Free Survival (PFS), Overall Survival (OS) than Gemcitabine, and a significantly higher response rate (27.6% vs. 10.9%). On the other hand, numerous clinical oncologists concur that FOLFRINOX is considerably more difficult to tolerate than GTX with regard to all known toxic side effects.

Although many variations are of course possible, based on the disclosure above, a proposed embodiment of the present invention for use with a chemotherapy treatment regimen for pancreatic cancer would include:

1) METFORMIN - 500 mg/day;

2) CELEBREX - 200 mg b.i.d. [variable depending on Ceruloplasmin levels];

3) NALTREXONE - 4.5 mg at bedtime;

4) TETRATHIOMOLYBDATE - 200 mg in divided doses every day;

5) MELATONIN - 10 mg/day.

To the foregoing non-chemotherapeutics, one or more nutraceuticals may be added for particular effects, in accordance with the present disclosure.

The present invention relates generally to a unique approach for the treatment of cancer combining the traditional forms of cancer treatment with the administration of naturally-occurring compounds and nutrients, i.e., "nutraceuticals". The treatment described herein is designed to inhibit, arrest, and/or otherwise disrupt, or, where appropriate, enhance endogenous signaling pathways and/or upregulate anti-angiogenic regulators (such as angiostatin) that, when dysregulated, lead to the formation or support the development of cancerous growth or tumors. In a preferred embodiment, the present invention is directed to compositions and methods for the treatment of cancers or tumors that are epithelial cell related. More particularly, the present invention is directed to compositions and methods suitable for the treatment of pancreatic cancer. In another embodiment, the present invention is designed to prevent the recurrence of cancer, in particular, pancreatic cancer by continuing the disclosed treatment regimen of naturally occurring compounds, nutrients, or nutraceuticals once it has been determined that the cancer or tumor is in remission or, in other words, there is no evidence of disease. A unique feature of the method and compositions described herein is that the combination of compounds and dosages of each can be tailored for each individual or patient in order to maximize the benefit realized for that particular patient. In this respect, the treatment regimen will be based on a pretreatment analysis of specific parameters, for example, on an analysis of blood or biopsied tissue obtained from the patient to be treated, prior to initiating the regimen. The present invention is directed to a unique integrative approach to cancer therapy, in which conventional oncology is merged with complementary modalities. The complementary aspect emphasizes the use of natural compounds and non-chemotherapeutic drugs to facilitate a synergistic approach in which each element of treatment, both conventional and non-conventional, is designed to inhibit angiogenesis and the oncogenic signaling transduction pathways within cancer cells and the intercellular signaling between tumor cells and their local cellular and biochemical micro- environment, with a strong emphasis on disruption of the intercellular signaling that fuels the ongoing processes of tumor angiogenesis.

EXAMPLES

The case described herein is a 69-year old woman diagnosed with stage III locally advanced pancreatic adenocarcinoma (LAPC). The patient's entire program involved a combination therapy regimen involving 80+ pills per day, however she experienced minimal gastrointestinal discomfort with this regimen.

The primary tumor (in her case, at the head of the pancreas) was inoperable due to encasement of a major blood vessel, in particular, the Superior Mesenteric Artery (SMA). The best that conventional treatment can usually offer is chemotherapy, in some cases with radiation, in an effort to reduce the tumor and prevent local/regional or distant metastatic spread of the disease. For most patients, the success of this treatment can extend lifespan beyond the predicted 3-4 months without treatment to 6- 1 1 months with treatment. In a minority of cases, patients with LAPC are "downstaged" from inoperable to operable disease, thus allowing for a pancreaticoduodenectomy (known as a Whipple procedure), or a total or distal pancreatectomy.

The treatment program described herein was designed for optimal response, and therefore to achieve the goal of downstaging so that the patient could undergo (in her case) a Whipple procedure, which enhances median survival and 5-year survival rates.

Diagnosis

The patient was diagnosed in May 2010, by endoscopic ultrasound-guided fine needle aspiration performed at New York-Presbyterian Weill Cornell Medical Center. The initial clinical impression from this procedure was of a pancreatic uncinate mass with vascular encasement that was difficult to aspirate. The biopsy confirmed the diagnosis as pancreatic ductal adenocarcinoma.

A first CT scan showed an ill-defined hypodense lesion extending inferiorly from the uncinate and contacting the transverse duodenum that extended slightly along the root of the small bowel mesentery. This is highly suspicious for carcinoma of the pancreas. The lesion measured 2.2 x 2.9 cm. The fat places around the adjacent superior mesenteric artery were indistinct, suggesting encasement. The inferior pancreaticoduodenal artery appeared encased. A PET scan was performed and indicated that the mass was hypermetabolic. These findings were compatible with the known clinical diagnosis of pancreatic carcinoma. Hypermetabolism was observed along the superior mesenteric artery, SUV 4.1 g/mL, corresponding to infiltration and encasement depicted on CT. Neither the CT nor the PET/CT demonstrated any definitive evidence of spread to regional lymph nodes or metastatic disease in the liver or anywhere else in the body. On CT scan, there was a calcification in the hepatic dome consistent with prior infection or trauma; on the PET scan, small, sub-centimeter hypodensities in the liver were uniformly without associated hypermetabolism. In sum, the patient's scans showed the presence of a roughly 3 cm. tumor at the pancreatic uncinate process at the head of the pancreas, with significant encasement of the SMA and an SUV of 1 1.8 g/mL, a very high reading that was clearly indicative of a hypermetabolic, highly active, malignant tumor of the pancreas. Consistent with this diagnosis of stage III, locally advanced pancreatic adenocarcinoma, chemotherapy was the initial treatment recommended.

First-Line Chemotherapeutic Treatment

The treatment regimen chosen was GTX (Gemcitabine, Docetaxel [Taxotere], and

Capecitabine [Xeloda]).

Development of GTX Therapy

Dr. Robert Fine of New York Presbyterian-Columbia University Medical Center first developed the GTX treatment regimen on the basis of extensive preclinical research demonstrating a powerful, sequence-dependent biochemical synergy among these three chemotherapeutics against pancreatic cancer (PC). Fine, et al., ASCO Annual Meeting, Gastrointestinal Cancer, PanCan. Abstract no. 575 (2002. This was demonstrated in a series of in vitro studies in which GTX induced apoptosis in a range of pancreatic cancer cell lines, including cells with both mutant p53 and activated RAS, and other cells with wild-type p53, suggesting that GTX would have activity beneficial for a wide range of pancreatic cancer patients with differing patterns of genetic perturbation. Dr. Fine began presenting his data at the American Society of Clinical Oncology (ASCO) Annual Meeting in 2001 ; his first presentation with mature human clinical data was in 2003. Fine, et al., Proc Am Soc Clin Oncol, 22:281 (2003). The study included 44 PC patients, 32 with metastatic disease (Stage IV) and 12 with locally advanced disease (stage III). Close to one-quarter of these patients (23%) had failed prior chemotherapy regimens. The response rate (all Partial Response (PR)) was 47%; with another 31% having had either Minor Response (MR) or stable disease (SD). Of the 15 patients who had a PR by the 3rd cycle, 3 patients had a clinical Complete Response (CR) by the 8th cycle. Most notable, however, was the outcome of the 12 patients with locally advanced disease. Eight of these 12 patients-67%— had sufficient clinical responses to GTX to be downstaged from inoperable to operable disease; all 8 had successful Whipple procedures. By contrast, a contemporaneous study conducted at Memorial Sloan Kettering Cancer Center in 2002, administered chemoradiation (mostly 5-FU or Gemcitabine with radiotherapy), included 87 patients with locally advanced PC, only 1 of whom was downstaged and underwent a Whipple Procedure. Kim, et al., J Gastrointest Surg., 6(5):763-9 (2002). Although the Fine study involved a small number of patients, the fact that two-thirds of the LAPC patients were downstaged, compared with only a fraction over 1% (1.15%) in the MSKCC study, suggested the possibility that GTX has unmatched potential to downstage locally advanced pancreatic cancer patients. Many confirmatory albeit single-arm studies of GTX since 2003 have continued to show similar results, demonstrating superiority compared with results being observed during the 2000s with a vast array of other chemotherapy and chemoradiation regimens. Chemotherapeutic Regimen

To limit initial toxicity, it was decided to phase in GTX by starting the patient on

Gemcitabine and Xeloda and then phasing in Taxotere. The regimen included XELODA 750 mg/m2/day b.i.d. (total daily dose = 1500 mg) on days 1- 14. On days 4 and 1 1, GEMCITABINE at 750 mg/m2/IV over 75 minutes, followed by low dose TAXOTERE at 30 mg/m2. After these two weeks, the patient then had a 7 day break before resuming the 21 -day cycle. During this first cycle, the patient did not begin to take TAXOTERE until Day 11 - so only the first Day 4 treatment of TAXOTERE was skipped. Thereafter, TAXOTERE was included according to the GTX protocol - on Days 4 and 1 1.

Nutraceutical/Non-Chemotherapeutic Drug Treatment Regimen

The goals of this protocol were to block angiogenesis, suppress copper serum levels, arrest the Warburg Effect and prohibit vasculogenic mimicry (see, e.g., Chen et al., Cancer Biol. & Therapy, 1 1(12):229-35 (201 1)). The protocol was customized for pancreatic cancer and complete pathway targeting components were added. This integrated program was implemented from the very beginning of the patient's treatment program, coincident with her initiation of chemotherapy with GTX. This regimen was continued, with only a few minor and occasional changes or additions, throughout her first-line therapy and beyond.

Vitamin D3 10,000 IU (2 x 5000 IU)

Zinc (Gluconate) 50 mg (2 25 mg)

Green Tea Extract - EGCG 2175 mg (3 x 725 mg)

Wobenzym® N Complex (3 times daily)

Naltrexone 4.5 mg

Metformin 500 mg

Tetrathiomolybdate 140 mg (7 x 20 mg)

Celebrex 400 mg

Acetyl- 1 -carnitine 1000 mg (2x 500 mg)

Vitamin B50 complex multivitamin w/ 500

mg Vitamin C 1500 mg (3 x 500 mg)

Co-Enzyme Q 10 100 mg

AHCC-Mushroom 500 mg

Bee Pollen Plus 400 mg (2 x 200 mg)

Co-El -NADH 5 mg

Flora Smart Probiotic

Fucoidan 300 mg

Graviola 3000 mg (4 x 750)

Imunal 1000 mg (2 x 500 mg)

Peak Immune4 1000 mg (4 x 250 mg)

Active Pectin 1000 g (2 x 500 mg)

PGP Complex (2 times daily)

Rhodiola 100 mg

Rosemaria 500 mg (2 x 250 mg)

Sulforaphane (from broccoli) 800 μg (2 x 400 μ )

Triphala 150 mg (3 x 50 mg)

The focus of the protocol was several fold: • to block, interrupt, or attenuate tumor angiogenesis or pathways that support angiogenesis, including disruption of signaling inducing vasculogenic mimicry;

• to reduce, inhibit, or reverse the mechanisms of chemo-resistance to chemotherapeutic drugs, in order to enhance effectiveness of chemotherapy, increase anti-tumor activity, increase pro- apoptotic activity;

• to support a metabolic shift from aerobic glycolysis (the "Warburg Effect") to glucose

oxidation, which promotes or renews a diminished capacity for undergoing apoptosis;

• to block, interrupt, or attenuate intracellular tumor cell signal transduction pathways that promote tumor cell growth;

· to inhibit intercellular signaling pathways that facilitate tumor invasion into local tissues and tumor metastasis;

• to reduce the toxic side effects of chemotherapy and any other active ingredients added to a treatment regimen; and

• to augment or enhance the patient's host defenses (particularly the host immune system), to improve general health and well-being.

As part of this effort, the patient was encouraged, based on the substantive literature of nutritional oncology, to maintain a low- fat diet with few if any animal products (roughly 15% of calories from fat); a low glycemic-index diet with no refined sugar products (given the role of insulin and insulin growth factors as signaling molecules in pancreatic cancer and other solid tumors);

moderate intake of whole-grain rather than refined grain products; no high-glycemic starchy foods; and an optimal intake of fresh fruits and vegetables replete with anti-tumor and anti-inflammatory phytonutrients.

In the development and implementation of the nutraceutical/non-chemotherapeutic drug protocol, the greatest care was taken to select natural compounds and non-chemotherapeutics that have been shown, in extensive and credible pre-clinical research, both in vitro and in vivo, to interrupt the intracellular and intercellular signaling pathways that are specifically involved in the pathogenesis and progression of pancreatic adenocarcinoma. This is an essential point, because although there are many pathways shared among different solid tumors and, to a lesser extent, hematologic cancers, certain pathways are particularly evident as drivers of the pathogenesis, angiogenesis, and progression of pancreatic cancer. This protocol sought to emphasize interruption of these specific pathways, and in so doing, nutraceutical compounds were selected along with some additional non-chemotherapeutic drugs that had already been shown (mostly in preclinical research) to possess these capacities.

Treatment Results

The patient's first cycle of GTX (without the first Day 4 treatment with i.v. TAXOTERE) began on Day 1. She continued to receiving full doses of GTX, on schedule every 3 weeks, for a total of six 21 -day cycles, with the last day of the sixth and last cycle on Day 164 (including the last 7-day break). Three of the 3-week cycles was considered to be one complete round; as such, the patient completed 2 complete rounds of GTX over the course of 18 weeks (4 ½ months).

By her own evaluation, the patient "tolerated GTX remarkably well, by all accounts." She had nothing worse than mild fatigue, and her blood counts never dropped to levels that required treatment delays or dose reductions. No scheduled treatments were delayed due to side effects or

myelosuppression.

The patient's first CT scan after beginning GTX was on Day 72, and a PET/CT scan followed on Day 87. These scans took place between her 3rd and 4th cycles of GTX. The CT scan showed that the tumor at the pancreatic uncinate was slightly larger by size than before, at 3.4 cm. x 2.4 cm, up from 2.9 cm. x 2.2 cm. There were no signs of any regional or distant metastatic spread on this scan. However, the PET/CT scan, showed that the maximum SUV was 3.5 g/mL, down from 1 1.8 g/mL on the initial diagnostic scan prior to beginning treatment. This marked reduction suggested a striking drop in metabolic activity of the tumor. Though PET scan SUV ratings are never hard-and- fast, an SUV at or below 2.5 g/mL is considered a non-malignant level of metabolic activity. The patient's SUV seemed headed in that direction, and given this dramatic drop in SUV, it is believed that the slightly increased size of the pancreatic mass could have been a sign of inflammatory responses associated with an ongoing process of tumor necrosis.

The patient's second set of scans - both CT and PET/CT - took place on Day 134 of treatment, after her 5th but before her 6th and last GTX treatment. The CT scan again showed no cancer in any anatomic site other than the head of the pancreas, and this time the tumor measured 2.2 cm. x 2.0 cm. - down from the previous 3.4 cm. x 2.4 cm. Now the tumor was not only smaller than the previous scan, but smaller than the initial scan (2.9 cm. x 2.2 cm.). The SUV was once again at 3.5 g/mL, which indicated a sustained relatively low level of metabolic activity. The GTX was clearly working, and the reduced tumor size did reinforce the theory that the prior increase in size was due more to inflammatory and/or edematous processes than to any growth of active tumor. By the same token, the lack of further drop in the SUV suggested a possible plateau in the efficacy of GTX.

Given these results, it was recommended that the patient go forward with her 6th cycle of GTX, but that she switch afterwards to FOLFIRINOX. Given her improvement, and her continued status as a Locally Advanced PC patient, it was possible that with more tumor regression, the degree of encasement of the SMA could be reduced sufficiently to enable downstaging to "operable" status. At that point, there had been a small degree of reduction in the area of encasement of the SMA, but not nearly enough to envision surgery. This factor was the primary consideration behind the decision to switch to FOLFIRINOX, which again had generated considerable enthusiasm at the 2010 ASCO meeting. The patient was informed that FOLFIRINOX was a more toxic regimen than GTX, associated with relatively more severe side effects, but the rationale for the change was persuasive and the patient had no hesitations.

The patient's first FOLFIRINOX treatment took place on Day 175 of treatment, the start of a 2-week cycle to commence on that day, with continuing cycles every 14 days. By the time of her next set of scans— her 4th— which took place on Day 232, she had already had four scheduled every- two-week cycles of FOLFIRINOX. These scans, taken after a significant number of FOLFIRINOX treatment cycles as well as her last GTX cycle, showed greater improvement. The CT scan demonstrated that the pancreatic tumor now measured 1.2 cm. x 1.3 cm, down from the prior 2.2 x 2.0 cm - a nearly 50% reduction in size just from the previous scan. This report described an ill- defined, hypodense tissue extending inferiorly from the pancreatic uncinate associated with mild vascular encasement. On the PET scan, the SUV had dropped one full point from the prior 3.5 g/mL to 2.5 g/mL, the number often used as a rough litmus of reversion to non-malignant status.

The FOLFIRINOX treatment had unquestionably advanced the initial gains made by GTX and taken them to another level. The mention that the vascular encasement of the SMA could now be described as "mild" suggested that the patient could be approaching operability. Her pancreatic surgeon agreed that her improvement was such that she could be considered a candidate for a Whipple procedure, but that there remained a degree of vascular encasement that made for less than optimal conditions for the procedure to go ahead at that time. It was agreed that her response to FOLFIRINOX was so exceptional that there was reason to hope that several more rounds of treatment could bring about the further reduction in tumor size and vascular encasement required for her to undergo surgery.

At that time, her physicians also discussed the option of radiation therapy to consolidate any further gains and provide an even more favorable condition for a safe and successful Whipple procedure. Among the goals of these treatments was to achieve the least degree of vascular encasement, increasing the odds that her status at surgery would not require vascular resection and reconstruction, with vascular grafting, for one or both vessels involved - the SMA and the portal vein, the latter requiring resection in the vast majority of cases.

As with GTX, the patient tolerated treatment with FOLFIRINOX extremely well, even though it was more toxic than GTX and did cause more fatigue. She would eventually undergo the planned six two-week cycles of FOLFIRINOX with no delays based on side effects or reduced blood counts. She did describe cumulative levels of fatigue, with slightly more severe symptoms of fatigue with each cycle, at the juncture between Grades 2 and 3. By the 4th cycle, she indicated that she began to "feel like I had the flu and was quite draggy". By the same token, she stated that, "I never really got sick or had nausea." The only medical intervention required was prescribed starting with the 4th cycle: Dexamethasone 4 mg for the first 4-5 days of the cycle to alleviate her increasingly severe fatigue. She reported that this treatment was extremely helpful and helped raise her energy levels during this portion of the cycle, when she usually had her worst degrees of fatigue.

The patient completed her FOLFIRINOX treatments on Day 259 of treatment. The patient had her subsequent scans on Day 273, two weeks after her last chemotherapy treatment cycle. The radiologist reporting the CT scan results could no longer put a measurement on the small residual tumor: "Evaluation of the pancreas reveals that previously noted uncinate process mass is less conspicuous on the current exam with virtually no peripancreatic stranding on the current study. No new lesion is identified. The pancreatic duct is normal."

The PET-CT report provided another level of validation: "Evaluation of the abdomen and pelvis demonstrates very minimal metabolic activity in the region of the uncinate process mass seen on prior studies. SUV measurements are noted up to 2.2 SUV g/mL, decreased slightly since the previous study. The previously noted lesion is not well seen on the low resolution CT images, and is also difficult to identify on the high resolution scan as described on that study."

In other words, the tumor had all but vanished. Her physician indicated that he could still see the area of tumor, and that there was still some degree of vascular encasement, but that the SUV of 2.2 g/mL made it possible that only necrotic or scar tissue remained but could not tell for sure until surgery was performed.

Conclusion

This patient's outcome is certainly at the far end of the treatment response curve by anyone's account, as she has had a near-complete tumor response, reduction of a high SUV rate indicating malignant levels of hypermetabolism to levels that are more consistent with benign tissue. She has had remarkably minimal side effects from two different polychemotherapy regimens, both of which are usually associated with far more severe side effects, with no treatment delays and no need for transfusion or other intervention to treat myelosuppression.

Her responses and capacity to tolerate treatment are entirely consistent with the intents and purposes of her integrative "protocol" which included a sizable number of natural compounds, nutrient supplements, and non-chemotherapeutic drugs all designed to optimize her chemotherapy response by offsetting the mechanisms of drug resistance, minimizing chemotherapy side effects, bringing other levels of anti-tumor activity by abrogating intracellular signal transduction pathways and the intercellular signaling involved in angiogenesis (without which tumor growth is impossible) as well as tumor invasion and metastatic spread. The fact that the tumor was reduced to barely detectible (though some tissue - whether malignant or necrotic is not certain— still hugged the Superior Mesenteric Artery) and that the metabolic activity was consistent with non-malignant tissue, strongly supports the view that the protocol had likely performed on all of the levels noted above.

While there is no question of the role of chemotherapy, and it is possible that the patient achieved some special benefit from the specific sequencing of GTX followed by FOLFIRINOX (an approach that may be worthy of additional investigation), three particularly unusual facets of this patient's treatment response make it all but certain that her complementary program played a pivotal role in the success of her drug treatments: (1) the patient's unusually minimal degree of adverse side effects; (2) the dramatic drop in metabolic activity on FDG-PET studies to 2.2 g/mL, which is within the non-malignant range (under 2.5 g/mL); and (3) the distinct possibility that the resultant difficult- to-measure remnant of the pancreatic tumor is entirely inactive necrotic or scar tissue. These are all exceedingly rare findings, even among those pancreatic cancer patients who have very good responses to chemotherapy.

The clinical results of this case study are remarkable for late stage pancreatic cancer. The novel integrative protocol approach described herein as a complement to the combination of emerging chemotherapy alternatives in GTX and FOLFIRINOX exceeded the goals predicted in advance.

Further analysis of these results and work with additional cancer patients have led to adjustments in the protocol for nutraceutical/non-chemotherapeutic agents and greater insight into how they may be used for positive outcomes in cancer treatment.

For example, a particularly preferred supplementary regimen for treatment of pancreatic cancer patients includes the following combination of compounds:

Zinc (Gluconate or Acetate) * 50 mg (2 25 mg)

Green Tea Extract - EGCG 3120 mg (6 520 mg)

Wobenzym® N Complex (3 times daily)

Naltrexone 4.5 mg

Metformin 500 mg

Tetrathiomolybdate 120 mg (4 x 30 mg)

Alpha Lipoic Acid 1200 mg (4 x 300 mg)

Acetyl- 1 -carnitine 1000 mg (2x 500 mg)

Genistein (pure) 8400 mg (6 x 1400 mg)

Milk Thistle Extract (Silymarin) 500 mg

Vitamin C 2000 mg (4 x 500 mg)

Vitamin E 1200 IU (3 x 400 IU)

Fucoidan 300 mg

Graviola 3000 mg (4 x 750)

Active Pectin 1000 g (2 x 500 mg)

Rhodiola 100 mg

Rosemaria 500 mg (2 x 250 mg)

Sulforaphane 800 μg (2 x 400 μ )

* no more that 50mg/day if Tetrathiomolybdate is being co-administered

While this complex combination was specifically designed with reference to actual cancer patients and background data, it was realized that the approach of addressing critical pathways and processes, particularly angiogenesis and other metabolic and signaling pathways, that are

dysregulated in cancer but may be returned toward normal state by the administration of nutraceutical and/or non-chemotherapeutic combinations, and thus have a anti- oncogenic effects, may be applied to design a large range of combination therapies that will be effective so long as they address at least a three abnormally activated or dysregulated pathways from among angiogenesis/vasculogenesis, tumor suppression dysregulation, cell cycle arrest (apoptosis disruption), and metabolic disruption (e.g., Warburg effect, anaerobic glycolysis, oxidative stress). The compositions and method of the present invention are designed to combine a range of compounds that address at least three endogenous processes. All patents, applications, and publications cited in the text above are incorporated herein by reference.

Other variations and embodiments of the invention described herein will now be apparent to those of skill in the art without departing from the disclosure of the invention or the coverage of the claims to follow.

Claims

1. A composition comprising three compounds, wherein each of said three compounds is capable of regulating a specific metabolic pathway or intracellular signaling pathway or intercellular signaling pathway implicated in the progression of cancer in an individual suffering from cancer, and wherein at least three such pathways are addressed.

2. The composition according to Claim 1, wherein said three compounds are nutraceutical or non-chemotherapeutic agents.

3. The composition according to Claim 2, wherein said three compounds are Naltrexone, Tetrathiomolybdate, and Metformin.

4. The composition according to Claim 3, wherein said composition additionally comprises one or more nutraceutical agents.

5. A composition comprising at least three different compounds, wherein at least one compound is selected from three of the following four tables, Tables 1-4:

Table 3 Boswellia Grape Seed Standardized Extract

Melatonin N- Acetyl Cysteine

Quercetin Zinc

Green Tea Milk Thistle Extract (Silymarin)

Extract - EGCG

6. The composition according to Claim 5, wherein two of said at least three different compounds are Tetrathiomolybdate and Metformin.

7. The composition according to Claim 5, wherein said at least three different compounds are Naltrexone, Tetrathiomolybdate, and Metformin.

8. The composition according to Claim 1, wherein said cancer is pancreatic cancer.

9. The composition according to Claim 5 comprising at least five different compounds, wherein at least one compound is selected from three of the four Tables 1, 2, 3, and 4.

10. The composition according to Claim 9, wherein said five different compounds are Curcumin, Genistein, Vitamin D3, N-acetyl Cysteine, and Green Tea Extract - EGCG.

1 1. The composition according to Claim 10, further comprising Naltrexone, Metformin, and Tetrathiomolybdate.

12. A composition comprising at least eight different compounds, with at least two compounds selected from each of Tables 1, 2, 3, and 4:

Baicalein Curcumin

Grape Seed Standardized Extract Melatonin

N-Acetyl Cysteine Pycnogenol

Quercetin Selenium

Vitamin D3 Green Tea Extract (or

epigallocatechin gallate)

Metformin Tetrathiomolybdate

Alpha Lipoic Acid Milk Thistle Extract (Silymarin)

Vitamin C Vitamin E

13. The composition according to Claim 12, wherein said composition comprises Curcumin, Genistein, Vitamin D3, Tetrathiomolybdate, N-acetyl Cysteine, Green Tea Extract or

epigallocatechin gallate, Metformin, and Naltrexone.

14. The composition according to Claim 13, wherein said composition further comprises Wobenzym® N enzyme blend.

15. The composition according to Claim 12 comprising at least thirteen different compounds, with at least two compounds being selected from each of Tables 1, 2, 3, and 4.

16. The composition according to Claim 15, wherein said thirteen different compounds include Curcumin, Genistein, Vitamin D3, Tetrathiomolybdate, N-acetyl Cysteine, Green Tea Extract - EGCG, Metformin, Naltrexone, and five additional different compounds selected from Tables 1, 2, 3, and 4.

17. A composition comprising at least eight different compounds, wherein at least one compound is selected from each of Tables 1, 2, 3, 4, 5 and 6:

Table 5

Acetyl- 1 -carnitine Fucoidan

Gravida Active Pectin

Rhodiola Rosemaria

Sulforaphane

18. The composition according to Claim 17 comprising at least fifteen different compounds, wherein at least one of said compounds is selected from each of Tables 1, 2, 3, and 4.

19. The composition according to Claim 18, wherein said at least fifteen compounds are selected such that at least one compound is selected from each of Tables 1, 2, 3, 4, 5, and 6.

20. The composition according to Claim 17, wherein said composition comprises at least twenty- two different compounds, wherein at least one of said compounds is selected from each of Tables 1 , 2, 3, 4, 5, and 6.

21. The composition according to Claim 17, wherein said composition comprises at least twenty- seven different compounds, wherein at least one of said compounds is selected from each of Tables

1, 2, 3, 4, 5, and 6.

22. The composition according to Claim 17, wherein said composition comprises at least twenty- eight different compounds, wherein at least one of said compounds is selected from each of Tables 1 ,

2, 3, 4, 5, and 6.

23. The composition according to Claim 17, wherein said composition comprises at least thirty- one different compounds, wherein at least one of said compounds is selected from each of Tables 1, 2, 3, 4, 5, and 6.

24. A composition for treatment of an individual suffering from pancreatic cancer, said composition comprising at least twenty-two compounds selected from the following compounds, or equivalents thereof:

Apigenin

Boswellia

Baicalein (Scutellaria baicalensis), Chinese Skullcap

Curcumin Grape Seed Extract

Melatonin

N- Acetyl Cysteine

Omega 3 - Fish Oil

Pycnogenol

Quercetin

Resveratrol

Selenium

Vitamin D3

Zinc

Green Tea Extract - EGCG

Wobenzym® N

Naltrexone

Metformin

Tetrathiomolybdate

Alpha Lipoic Acid

Acetyl- 1 -carnitine

Genistein (pure)

Milk Thistle Extract (Silymarin)

Vitamin C

Vitamin E

Fucoidan

Graviola

Active Pectin

Rhodiola

Pvosemaria

Sulforaphane.

25. A composition for treatment of an individual suffering from pancreatic cancer, said composition comprising at least twenty -two compounds selected from the following compounds, or equivalents thereof, in sufficient sufficient dosages to provide the listed daily amounts:

Milk Thistle Extract (Silymarin) 500 mg

Vitamin C 2000 mg

Vitamin E 1200 IU

Fucoidan 300 mg

Gravida 3000 mg

Active Pectin 1000 g

Rhodiola 100 mg

Rosemaria 500 mg

Sulforaphane 800 μg.

26. The composition according to Claim 24 or Claim 25, wherein said composition comprises at least twenty-seven different compounds.

27. The composition according to Claim 24 or Claim 25, wherein said composition comprises at least twenty-eight different compounds.

28. The composition according to Claim 24 or Claim 25, wherein said composition comprises at least thirty-one different compounds.

29. Use of a composition in the manufacture of a medicament for treating an individual suffering from cancer, said composition comprising at least three different compounds, wherein at least one compound is selected from three of the following four tables, Tables 1-4:

Quercetin Selenium

Vitamin D3 Green Tea Extract - EGCG

Metformin Tetrathiomolybdate

Alpha Lipoic Acid Milk Thistle Extract (Silymarin)

Vitamin C Vitamin E

30. The use according to Claim 29, wherein said cancer is of epithelial origin.

31. The use according to Claim 29, wherein said cancer is pancreatic cancer.

32. The use according to Claim 29, wherein two of said at least three different compounds are Tetrathiomolybdate and Metformin.

33. The use according to Claim 29, wherein said at least three different compounds are

Naltrexone, Tetrathiomolybdate, and Metformin.

34. The use according to Claim 29, wherein said composition comprises at least five different compounds, and wherein at least one compound is selected from each of the four Tables 1, 2, 3, and 4.

35. The use according to Claim 29, wherein said composition comprises at least eight different compounds, and wherein at least two of said compounds are selected from each of Tables 1, 2, 3, and 4.

36. The use according to Claim 29, wherein said composition comprises at least thirteen different compounds, and wherein at least two of said compounds are selected from each of Tables 1, 2, 3 and 4.

37. Use of a composition in the manufacture of a medicament for treating an individual suffering from cancer, said composition comprising at least eight different compounds, wherein at least one of said compounds is selected from each of the following Tables 1, 2, 3, 4, 5, and 6:

Table 5

Acetyl- 1 -carnitine Fucoidan

Gravida Active Pectin

Rhodiola Rosemaria

Sulforaphane

38. The use according to Claim 37, wherein said cancer is of epithelial origin.

39. The use according to Claim 37, wherein said cancer is pancreatic cancer.

40. The use according to Claim 37, wherein two of said at least three different compounds are Tetrathiomolybdate and Metformin.

41. The use according to Claim 37, wherein said at least three different compounds are

Naltrexone, Tetrathiomolybdate, and Metformin.

42. The use according to Claim 37, wherein said composition comprises at least fifteen different compounds, and wherein at least one of said compounds is selected from each of Tables 1, 2, 3, 4, 5, and 6.

43. The use according to Claim 37, wherein said composition comprises at least twenty- two different compounds, and wherein at least one of said compounds is selected from each of Tables 1 , 2, 3, 4, 5, and 6.

44. The use according to Claim 37, wherein said composition comprises at least twenty-seven different compounds, and wherein at least one of said compounds is selected from each of Tables 1 , 2, 3, 4, 5, and 6.

45. The use according to Claim 37, wherein said composition comprises at least twenty-eight different compounds, and wherein at least one of said compounds is selected from each of Tables 1 , 2, 3, 4, 5, and 6.

46. The use according to Claim 37, wherein said composition comprises at least thirty-one different compounds, and wherein at least one of said compounds is selected from each of Tables 1 , 2, 3, 4, 5, and 6.

47. Use of a composition in the manufacture of a medicament for treating an individual suffering from pancreatic cancer, said composition comprising at lest twenty -two compounds selected from the following:

Apigenin

Boswellia

Baicalein (Scutellaria baicalensis), Chinese Skullcap

Curcumin

Grape Seed Extract

Melatonin

N- Acetyl Cysteine

Omega 3 - Fish Oil

Pycnogenol

Quercetin

Resveratrol

Selenium

Vitamin D3

Zinc

Green Tea Extract - EGCG

Wobenzym® N

Naltrexone

Metformin

Tetrathiomolybdate

Alpha Lipoic Acid

Acetyl- 1 -carnitine

Genistein (pure)

Milk Thistle Extract (Silymarin)

Vitamin C Vitamin E

Fucoidan

Gravida

Active Pectin

Rhodiola

Rosemaria

Sulforaphane.

48. Use of a composition in the manufacture of a medicament for treating an individual suffering from pancreatic cancer, said composition comprising at least twenty -two compounds selected from the following compounds, or equivalents thereof, in sufficient sufficient dosages to provide the listed daily amounts:

Wobenzym® N Complex

Naltrexone 4.5 mg

Metformin 500 mg

Tetrathiomolybdate 120 mg

Alpha Lipoic Acid 1200 mg

Acetyl- 1 -carnitine 1000 mg

Genistein (pure) 8400 mg

Milk Thistle Extract (Silymarin) 500 mg

Vitamin C 2000 mg

Vitamin E 1200 IU

Fucoidan 300 mg

Gravida 3000 mg

Active Pectin 1000 g

Rhodiola 100 mg

Rosemaria 500 mg

Sulforaphane 800 μg.

49. The use according to Claim 47 or Claim 48, wherein said composition comprises at least twenty-seven different compounds.

50. The use according to Claim 47 or Claim 48, wherein said composition comprises at least twenty-eight different compounds.

51. The use according to Claim 47 or Claim 48, wherein said composition comprises at least thirty-one different compounds.

52. A method for treating an individual suffering from pancreatic cancer comprising administering to said individual a composition comprising three compounds, wherein each of said three compounds is capable of regulating a specific metabolic pathway or intracellular signaling pathway or intercellular signaling pathway implicated in the progression of cancer in an individual suffering from cancer, and wherein at least three such pathways are addressed.

53. The method according to Claim 52, wherein said three compounds are nutraceutical or non- chemotherapeutic agents.

54. The method according to Claim 53, wherein said three compounds are Naltrexone, Tetrathiomolybdate, and Metformin.

55. The method according to Claim 54, wherein said composition additionally comprises one or more nutraceutical agents.

56. A method for treating an individual suffering from pancreatic cancer comprising administering to said individual a composition comprising at least three different compounds, wherein at least one compound is selected from three of the following four tables, Tables 1-4:

Table 4

Melatonin Metformin

Naltrexone.

57. The method according to Claim 56, wherein two of said at least three different compounds are Tetrathiomolybdate and Metformin.

58. The method according to Claim 56, wherein said at least three different compounds are Naltrexone, Tetrathiomolybdate, and Metformin.

59. The method according to Claim 56, wherein said composition comprises at least five different compounds, wherein at least one compound is selected from each of the four Tables 1, 2, 3, and 4.

60. The method according to Claim 59, wherein said five different compounds are Curcumin, Genistein, Vitamin D3, N-acetyl Cysteine, and Green Tea Extract - EGCG.

61. The method according to Claim 60, said composition further comprising Naltrexone, Metformin, and Tetrathiomolybdate.

62. A method for treating an individual suffering from pancreatic cancer comprising administering to said individual a composition comprising at least eight different compounds, wherein at least two of said compounds are selected from each of Tables 1, 2, 3, and 4:

Alpha Lipoic Acid Milk Thistle Extract (Silymarin)

Vitamin C Vitamin E

63. The method according to Claim 62, wherein said composition comprises Curcumin, Genistein, Vitamin D3, Tetrathiomolybdate, N-acetyl Cysteine, Green Tea Extract or

epigallocatechin gallate, Metformin, and Naltrexone.

64. The method according to Claim 63, wherein said composition further comprises

Wobenzym® N enzyme blend.

65. The method according to Claim 62, said composition comprising at least thirteen different compounds, with at least two compounds being selected from each of Tables 1, 2, 3, and 4.

66. The composition according to Claim 65, wherein said thirteen different compounds include Curcumin, Genistein, Vitamin D3, Tetrathiomolybdate, N-acetyl Cysteine, Green Tea Extract - EGCG, Metformin, Naltrexone, and five additional different compounds selected from Tables 1, 2, 3, and 4.

67. A method for treating an individual suffering from pancreatic cancer, said method comprising administering a composition comprising at least eight different compounds, wherein at least one of said compounds is selected from each of Tables 1, 2, 3, 4, 5 and 6:

Table 6

Wobenzym®N Medizym® enzyme

enzyme blend blend.

68. The method according to Claim 67, said composition comprising at least fifteen different compounds, wherein at least one of said compounds is selected from each of Tables 1, 2, 3, and 4.

69. The method according to Claim 68, wherein said at least fifteen compounds are selected such that at least one compound is selected from each of Tables 1, 2, 3, 4, 5, and 6.

70. The method according to Claim 67, wherein said composition comprises at least twenty-two different compounds, and wherein at least one of said compounds is selected from each of Tables 1 , 2, 3, 4, 5, and 6.

71. The method according to Claim 67, wherein said composition comprises at least twenty- seven different compounds, and wherein at least one of said compounds is selected from each of Tables 1, 2, 3, 4, 5, and 6.

72. The method according to Claim 67, wherein said composition comprises at least twenty-eight different compounds, and wherein at least one of said compounds is selected from each of Tables 1 , 2, 3, 4, 5, and 6.

73. The method according to Claim 67, wherein said composition comprises at least thirty-one different compounds, and wherein at least one of said compounds is selected from each of Tables 1 , 2, 3, 4, 5, and 6.

74. A method for treating an individual suffering from pancreatic cancer comprising

administering to said individual a composition comprising at least twenty -two compounds selected from the following compounds, or equivalents thereof:

Apigenin

Boswellia

Baicalein (Scutellaria baicalensis), Chinese Skullcap

Curcumin

Grape Seed Extract

Melatonin

N- Acetyl Cysteine

Omega 3 - Fish Oil

Pycnogenol Quercetin

Resveratrol

Selenium

Vitamin D3

Zinc

Green Tea Extract - EGCG

Wobenzym® N

Naltrexone

Metformin

Tetrathiomolybdate

Alpha Lipoic Acid

Acetyl- 1 -carnitine

Genistein (pure)

Milk Thistle Extract (Silymarin)

Vitamin C

Vitamin E

Fucoidan

Graviola

Active Pectin

Rhodiola

Rosemaria

Sulforaphane.

75. A method for treating an individual suffering from pancreatic cancer comprising administering to said individual a composition comprising at least A composition for treatment of an individual suffering from pancreatic cancer, said composition comprising at least twenty-two compounds selected from the following compounds, or equivalents thereof, in sufficient sufficient dosages to provide the listed daily amounts: Compound amount/day

Apigenin 50 mg

Boswellia 1600 mg

Baicalein, Chinese Skullcap 200 mg

Curcumin 2400 mg

Grape Seed Extract 100 mg

Melatonin 10 mg

N-Acetyl Cysteine 5400 mg

Omega-3 Fish Oil 3000 mg

Pycnogenol 100 mg

Quercetin 250 mg

Resveratrol 250 mg

Selenium 400 μg

Vitamin D3 10,000 IU

Zinc 50 mg

Green Tea Extract - EGCG 3120 mg

Wobenzym® N Complex

Naltrexone 4.5 mg

Metformin 500 mg

Tetrathiomolybdate 120 mg

Alpha Lipoic Acid 1200 mg

Acetyl- 1 -carnitine 1000 mg

Genistein (pure) 8400 mg

Milk Thistle Extract (Silymarin) 500 mg

Vitamin C 2000 mg

Vitamin E 1200 IU

Fucoidan 300 mg Graviola 3000 mg

Active Pectin 1000 g

Rhodiola 100 mg

Pvosemaria 500 mg

Sulforaphane 800 μg.

76. The method according to Claim 75 or Claim 76, wherein said composition comprises at least twenty-seven different compounds.

77. The composition according to Claim 75 or Claim 76, wherein said composition comprises at least twenty-eight different compounds.

78. The composition according to Claim 75 or Claim 76, wherein said composition comprises at least thirty-one different compounds.

79. The method according to Claim 75 or Claim 76, wherein said individual is undergoing additional treatment comprising administration of one or more chemotherapeutic agents.

80. The method according to Claim 79, wherein said additional treatment comprises administration of Gemcitabine, Docetaxel, Rigosertib, Capecitabine, and combinations thereof.

81. The method according to Claim 80, wherein said additional treatment comprises administration of Gemcitabine.

82. The method according to Claim 79, wherein said additional treatment comprises administration of 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX).

83. The method according to Claim 79, wherein said additional treatment comprises administration of 5-fluorouracil.

84. A method for treating an individual suffering from pancreatic cancer comprising:

(a) detecting abnormally elevated levels in said individual of one or more pro-angiogenic regulators selected from the group consisting of VEGF, MMP-9, MMP-2, TNF-a, IGF- 1, CXCR4, TGF-β, EGFR, IL-Ι β, IL-6, bFGF, PDGF-BB, IL-8, Angiogenin, IL-la, and Leptin, and/or detecting abnormally low levels of angiostatin or other anti- angiogenic regulators in said individual;

(b) detecting abnormal or undesirable activation of at least three metabolic, intercellular signaling, or intracellular signaling pathways identified in groups I, II, III, IV, and V, below, and wherein abnormal or undesirable activation is detected for pathways in at least three separate groups:

PI3K/AKT/mTOR

enzyme or endocrine levels abnormal

(c) administering a composition comprising at least one compound selected from the group of compounds corresponding to the abnormalities detected in (a) and (b) according to the following table, said compound being administered in an amount effective to alter said abnormal state toward a normal state of an individual not exhibiting pancreatic cancer: