WO2020242496A1 - Procédé de traitement du cancer du pancréas - Google Patents

Procédé de traitement du cancer du pancréas Download PDF

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Publication number
WO2020242496A1
WO2020242496A1 PCT/US2019/034966 US2019034966W WO2020242496A1 WO 2020242496 A1 WO2020242496 A1 WO 2020242496A1 US 2019034966 W US2019034966 W US 2019034966W WO 2020242496 A1 WO2020242496 A1 WO 2020242496A1
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digitoxin
cells
vitamin
cancer
combination
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PCT/US2019/034966
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English (en)
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Bette Silver POLLARD
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Pollard Bette Silver
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • a method of treating pancreatic cancer and other cancers in a patient, including a cystic fibrosis (CF) patient, is disclosed, wherein a combination of two drugs, digitoxin and Intravenous vitamin C or parental Vitamin C (PVC), will act synergistically to limit toxic side effects and to inhibit HSP27 when administered together to a patient in need thereof.
  • CF cystic fibrosis
  • Pancreatic cancer is one of the deadliest forms of cancer in the world, and approved therapies have a 5-year survival rate of only 6%
  • Cystic fibrosis is also a life-limiting proinflammatory genetic illness due to mutations in the CFTR gene, which predisposes to increased risk of pancreatic cancer in CF patients. The occurrence of both illnesses together, although relatively infrequent, has motivated us to search for therapeutic solutions that would impact less severely on the already profoundly compromised cystic fibrosis patient.
  • pancreatitis The most consistent risk factor for pancreatic cancer is inflammation due to chronic pancreatitis
  • Pancreatitis is caused principally by sustained environmental insults from alcoholism and smoking. Chronic pancreatitis is less frequently caused by intrinsic inflammation due to genetic mutations.
  • CF cystic fibrosis
  • PRSS1 the trypsinogen gene
  • SPINK1 pancreatic secretory trypsin inhibitor
  • CFTR the gene responsible for cystic fibrosis
  • the common factors associated with chronic inflammation in the pancreas include chronic activation of signaling pathways driven by NFKB, the master mediator of inflammation, and by COX2 [3-6] While the median age of onset of pancreatic cancer is 71 YO [7, 8], CF is associated with a much earlier age of onset [9] Although pancreatic cancer is relatively infrequent in the CF population, the low likelihood of CF patients living to older ages has resulted in calculating the odds ratio to be 31.5 for development of pancreatic cancer in CF patients [9] As for most other cancers, CF -associated pancreatic cancer is associated with enhanced mutagenesis and rapid accumulation of mutations, including KRAS, TP53, ID-l/ID
  • CF is also associated with an increased risk of other cancers, both in the digestive tract [9, 12] and lung [13, 14], as well as breast [15]
  • an additional problem for CF patients is the threat of confronting the risks of yet additional life-limiting neoplasms, including pancreatic cancer.
  • CFPAC-1 cystic fibrosis pancreatic adenocarcinoma cell line
  • This cell line was originally isolated from a pancreatic metastasis to the liver, following the post-mortem examination of a Caucasian 26 year old male with CF.
  • This cell was named CF for cystic fibrosis, and PAC for Pancreatic Cancer.
  • the CF patient was homozygous for the common [delF508]CFTR cystic fibrosis mutation.
  • CFPAC-1 cells are also homozygous for a SMAD4 deletion.
  • the KRAS and TP53 mutations have also characterized the CFPAC-1 cell as among the most molecularly representative of a highly aggressive pancreatic cancer [18]( See Figure 1).
  • a further advantage of this cell line is the availability of CFPAC-1 daughter cells which have been stably rescued by retrovirally-mediated transfection of [wildtype]CFTR (vzz, CFPAC-l(PLJ-4.7 cells). Essentially, the transfection of [wildtype] CFTR into CFPAC-1 cells gives these cells the status of being just a common pancreatic cancer cell that is irrelevantly heterozygous for CF.
  • cancers affected were cancers of the pancreas, prostate, stomach or gastric cancer, colorectal, head and neck, renal, ovarian cancer and others [19-22]
  • the experiment found that digitoxin reduced HSP27/HSPB1, and also that TNF-alpha combined with digitoxin further and significantly reduced HSPB1. (See Figure 2; unpublished results).
  • Digitoxin is one of the most potent known, patient- tested drugs used as a treatment for cystic fibrosis, which we first identified in studies of CF lung epithelial cells [23] Digitoxin’s primary mechanism of action is to block the interaction between the TNFa/TNFRl and TRADD, the first intracellular adaptor for TNFa signaling to NFKB [24] The role of [wildtype]CFTR in non-CF patients is to ensure that TRADD is conditionally destroyed in the proteasome, thus tonically inhibiting proinflammatory signaling [25] Mutant CFTR fails in this task, leading to constitutive NFKB activation and high levels of downstream IL-8 expression.
  • Digitoxin also has potent carcinotoxic activity in vitro [27]
  • PVC alone, or in combination with other approved drugs has been tested in multiple tumor types [28], and in pancreatic cancer patients where in some trials it was found to prolong survival [29-33]
  • the challenge facing PVC as a sole therapy has been thought to be that of achieving an adequate duration of a sufficiently high concentration vitamin C in the vicinity of the tumor [35, 36]
  • mixing PCV with gemcitabine has yielded some improvement in mean-time -to-progression and to mean over-all survival [33]
  • treatment with gemcitabine involves significant toxic side effects.
  • Digitoxin is a less toxic Parp inhibitor [27] By comparison, there are no extremes in toxic side effects from either digitoxin or PVC, making the possibility of
  • CFPAC-1(P) cells delF508/delF508), CFPAC-1(4.7) cells (retrovirally transfected with [wildtypeJCFTR), and CFPAC-1 (6) cells (transfected with a control retrovirus) were obtained from Dr. Raymond Frizzell (University of Pittsburg). Digitoxin and vitamin C were obtained from Sigma. Cells were cultured under conditions as previously described [37] For the current experiments, CFPAC-1(P) and CFPAC-1(6) cells were plated at a density of 50,000 cells/well, in 24 well Costar plates, and allowed to grow for 48 hours in different conditions. Media and drugs were replaced by fresh media and drugs after 24 hours. CFPAC-1 (4.7) cells were plated at 10,000 cells/well and cultured for 48 hours exactly as for the other cell lines. [0012] Preparation of vitamin C and digitoxin
  • Vitamin C was prepared as a stock solution in PBS, and titrated to pH 7.4 with NaOH. Thereafter, Vitamin C was diluted in PBS to appropriate concentrations in culture medium. Vitamin C was tested at concentrations of 2, 4 and 8 mM. Digitoxin was prepared as a 6 mg/ml stock solution in 95% ETOH and propylene glycol, and stored at -20°C. Concentrations of digitoxin were analyzed using an ELISA kit from Creative Diagnostics (Shirley, NY), originally developed for digoxin, but adapted by us for measurement of digitoxin. The LLOD (lower limit of detection) was 0.1 ng/ml. For each experiment, digitoxin was freshly diluted as a stock solution in DMSO, and tested at final concentrations of 1, 2, 10, and 30 nM. All experiments included a vehicle control.
  • IL-8 was assayed using a human IL-8/CXCL8 Quantikine ELISA kit (D8000C) from R&D Systems. Cell viability was assayed by the MTT method, using a kit from ThermoFisher (MTT: (3-(4,5 dimethylthylthiazol-2-yl)-2,5 diphenyltetrazolium bromide), Catalog number M6494).
  • MTT ThermoFisher
  • the Chou-Talalay method was used to compute the combination index (Cl), and further quantified using the Fa-CI and Fa-DRI plots [38] Data were derived from experiments using the constant-ratio of drug combinations. In this case the IC50 values for digitoxin and vitamin C were mixed together, serially-2-fold diluted, and incubated with cells, as described. The actual IC50 mixture was designed to be the middle of a 7 dilution series experiment. The analysis was carried out using the CompuSyn program (Chou TC. Martin N, CompuSyn for drug combinations, Paramus, NJ: ComboSyn, 2005).
  • Figure 1 shows a heatmap linking CFPAC-1 cells with typical pancreatic adenocarcinoma tumor cells
  • Figure 2 shows the influence of digitoxin on mRNA expression in human prostate cancer PC3 cells
  • Figure 3 shows the influence of digitoxin on mRNA expression in in vivo rat castration- resistant prostate tumor cells
  • Figure 4 shows the influence of digitoxin and vitamin C on the growth of CFPAC-1 cells
  • Figure 5 shows Fa-CI and Fa-DRI plots for CFPAC-1 (P) cells treated with digitoxin and vitamin C;
  • Figure 6 shows Fa-CI and Fa-DRI plots for CFPAC-1 (6.0) cells treated with digitoxin and vitamin C
  • Figure 7 shows Fa-CI and Fa-DRI plots for CFPAC-1 (4.7) cells treated with digitoxin and vitamin C;
  • Figure 8 shows the chemical structure of digitoxin
  • Figure 9 shows the chemical structure of vitamin C.
  • Figure 1 shows a heatmap linking CFPAC-1 cells with typical pancreatic adenocarcinoma tumor cells. From Yu K, Chen B, Aran B, Goldstein T, Sirota M. Comprehensive transcriptomic analysis of cell lines as models of primary tumor samples across 22 tumor cell types. BioRxiv http://dx.doi.org/10.1101/422592 (2016).
  • Figure 1A shows the effects of digitoxin alone, titrated in range of 0-30 nM, on the survival of parental CFPAC-1 (P) cells in culture for two days. In this concentration range the apparent IC50 for digitoxin is ca. 5 nM.
  • Figure IB shows a titration of vitamin C alone, over the range of 0-8 mM, or in combination with 30 nM digitoxin. The MTT value for digitoxin-only at 0 mM vitamin C is close to the 30 nM level of MTT in Figure 1A.
  • Figure 1 C and D show equivalent data for the transfection control CFPAC-1 (6) cell line.
  • Figure 1 E and F show equivalent data for the CFPAC-1 (PLJ-4.7) cell corrected with [wildtypeJCFTR. In all three cases, the apparent IC50 for this specific combination of digitoxin and vitamin C is in the range of the 3 mM vitamin C mark.
  • the first line in Table 1 shows synergistic data for digitoxin and vitamin C for all three cell types.
  • the IC50 for digitoxin alone (“mono”) is calculated to be 27.27 nM
  • the IC50 for vitamin C alone (“mono”) is calculated to be 5.6 mM.
  • combo the IC50 for digitoxin is reduced to 5.6 nM
  • the IC50 for vitamin C is reduced to 1.52 mM.
  • the Combination Index (“CF’) is 0.61.
  • Cl is a measure of synergy in which any value less than 1.0 indicates a synergistic effect.
  • the combination of digitoxin with vitamin C lowers the effective concentration of vitamin C by ca 73%.
  • the second line in Table 1 shows similar synergy calculations for mock-transfected CFPAC-1 (6) cells. For these cells, the IC50 for digitoxin alone (“mono”) is calculated to be 27.27 nM, and the IC50 for vitamin C alone (“mono”) is again calculated to be 5.6 mM. However, in combination (“combo”), the IC50 for digitoxin is reduced to 3.29 nM, and the IC50 for vitamin C is reduced to 0.99 mM. Consistently, the Combination Index (“CF’) is 0.40. Thus, for CFPAC-1 (P) cells the combination of digitoxin with vitamin C lowers the effective concentration of vitamin C by ca 88%.
  • the third line in Table 1 shows similar synergy calculations for [ wi 1 dtype] C FTR-tran sfected CFOC-1 (PLJ-4.7) cells.
  • Figure 2 shows the influence of digitoxin on mRNA expression in human prostate cancer PC3 cells for A, HSPB1; B, RBFOX2; and C, HSPB1/RBFOX2 ratio.
  • PC3 cells were grown for three days in media containing either no additions, 10 nM digitoxin, 10 ng/ml TNFa, or both digitoxin and TNFa in combination. Units are transcripts per kilobase million (TPM). Statistical significance is taken as P ⁇ 0.05 (exact test), based on a one-tailed t-test.
  • Figure 3 shows the influence of digitoxin on mRNA expression in in vivo rat castration- resistant prostate tumor cells A, Hspbl; B, Rbfox2; and C, Hspbl/Rbfox2 ratio. Passaged tumors in rats were treated with 0.03 mg/kg digitoxin for 30 days. Units are transcripts per kilobase million. (TPM). Statistical significance is taken as P ⁇ 0.05 (exact test), based on a one-tailed t-test.
  • Figure 4 shows the influence of digitoxin and vitamin C on growth of CFPAC-1 cells. A and B are data for digitoxin alone and digitoxin + Vitamin C for CFPAC1-(P).
  • (P) is the parental line that is homozygous for [F508del ⁇ T .
  • C and D are data for digitoxin alone and digitoxin + Vitamin C for CFPACl-(6).
  • (6) is the parental line which has been mock- transfected with an empty retroviral vector.
  • E and F are data for digitoxin alone and digitoxin + Vitamin C for CFPACl-(4.7).
  • (4.7) also known as (PLJ-4.7), is the parental line which has been transfected with a retrovirus carrying [1 ⁇ 47 y/>e]CFTR.
  • FIG. 5 shows Fa-CI and Fa-DRI plots for CFPAC-1 (P) cells treated with Digitoxin and Vitamin C.
  • the colored symbols are experimental datapoints.
  • the black symbols are computer simulation of the experimental points.
  • Fa refers to fraction of cells that are affected synergistically (A) and have a favorable dose reduction index due to the synergy (B).
  • FIG. 6 shows Fa-CI and Fa-DRI plots for CFPAC-1 (6.0) cells treated with Digitoxin and Vitamin C.
  • the colored symbols are experimental datapoints.
  • the black symbols are computer simulation of the experimental points.
  • Fa refers to fraction of cells that are affected synergistically (A) and have a favorable dose reduction index due to the synergy (B).
  • FIG. 7 shows Fa-CI and Fa-DRI plots for CFPAC-1 (4.7) cells treated with Digitoxin and Vitamin C.
  • the colored symbols are experimental datapoints.
  • the black symbols are computer simulation of the experimental points.
  • Fa refers to fraction of cells that are affected synergistically (A) and have a favorable dose reduction index due to the synergy (B).
  • Fractional Combination Index (Fa-CI) and the Fractional Dose Reduction Index (Fa-DRI) show how closely the experimental points resemble the computer simulation for the derived values of Cl and DRI.
  • Figure 2 A shows CFPAC-1 (P) data for Fa-CI
  • Figure 2B shows the CFPAC-1 (P) data for Fa-DRI. They are the inverse of each other, and indicate that between 30 and 70% of the cells are responding to the synergistic effect of digitoxin and vitamin C. In the case of Fa-CI, synergy is below the dotted line. In the case of FA-DRI, favorable dose reduction due to synergy is above the line.
  • Equivalent analyses are shown in Figure 3 for mock-transfected CFPAC-1 (6), and in Figure 4 for CFPAC-1 (PLJ-4.7) cells.
  • Cancer often uses the redundancy of signaling pathways to eventually circumvent the suppressive effects of drugs acting on single sites of interference [39] By targeting multiple pathways and hoping for synergism, the question is how to decide what dose ratio optimizes the synergy [39, 40] Polypharmacy drugs which have multiple mechanisms of action, or mixtures of drugs that individually address single sites of action, provide strategies to address this problem and defend against recurrence.
  • Digitoxin is one of the most potent known, patient- tested anti-inflammatory drugs, which we first identified in studies of CF lung epithelial cells [23] Digitoxin’ s mechanism of action is to block the interaction between the TNFa/TNFRl and TRADD, the first intracellular adaptor for TNFa signaling to NFKB [24] Within its conventionally narrow therapeutic window, digitoxin has minimal effects on normal cells, but selectively kills tumor cells [27] By synergistically lowering the IC50 for digitoxin from ca. 27 nM to ca. 5.6 nM, the result is a widening of the therapeutic window for killing pancreatic cancer cells.
  • a method of treating pancreatic cancer (PAC) in a cystic fibrosis (CF) patient comprises administering a combination of digitoxin and parenteral vitamin C (PVC) to a patient in need thereof.
  • PAC pancreatic cancer
  • PVC parenteral vitamin C
  • the amount of digitoxin in the extracellular tissue is in a range of 1 to 30 nanomol (nM), preferably 1 to 20 nM, more preferably 1 to 10 nM, particularly preferably about 5 nM.
  • a pharmaceutical formulation comprising an effective amount of a combination of digitoxin and parenteral vitamin C (PVC) for use in the treatment of cancer in combination with chemotherapy, radiation, and/or immunotherapy.
  • PVC parenteral vitamin C
  • a method of lowering hsp27(Bl) in a mammalian cell comprising: administering digitoxin.
  • Clause 7 A pharmaceutical composition containing digitoxin for use in cancer therapy for the suppression of chemoresi stance formation or in the treatment of cystic fibrosis.
  • CFTR Controls the Activity of NF-kappaB by Enhancing the Degradation of TRADD.
  • Cellular physiology and biochemistry international journal of experimental cellular physiology, biochemistry, and pharmacology. 2016;40(5): 1063-78. Epub 2016/12/14. doi: 10.1159/000453162. PubMed PMID: 27960153.

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Abstract

L'invention concerne un procédé de traitement du cancer du pancréas (PAC) chez des patients atteints de fibrose kystique (CF), une association de deux médicaments, de la digitoxine et de la vitamine C par voie parentérale (PVC) étant administrée au patient. L'association des deux médicaments peut inhiber fortement la croissance cellulaire dans une lignée cellulaire unique d'adénocarcinome pancréatique associé à une fibrose kystique, CFPAC-l(P). Lors de la correction de l'état de CF par transfection de ces cellules avec le CFTR de type sauvage (c'est-à-dire, CFP AC-1 (PL J-4,7)), la sensibilité à ces deux médicaments, individuellement ou en association, reste identique. Cependant, leur association est synergique, ce qui permet d'obtenir des valeurs IC50 (concentration inhibitrice) apparentes inférieures pour chaque médicament. La CI50 de la vitamine C est réduite de 75 à 88 %, et la CI50 de la digitoxine est réduite de 50 %.
PCT/US2019/034966 2019-05-31 2019-05-31 Procédé de traitement du cancer du pancréas WO2020242496A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040082521A1 (en) * 2002-03-29 2004-04-29 Azaya Therapeutics Inc. Novel formulations of digitalis glycosides for treating cell-proliferative and other diseases
US20060041109A1 (en) * 2004-06-24 2006-02-23 Wisconsin Alumni Research Foundation Neoglycorandomization and digitoxin analogs
US20140187505A1 (en) * 2002-05-28 2014-07-03 Bette Pollard Cardiac Glycosides to Treat Cystic Fibrosis and Other IL-8 Dependent Disorders

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040082521A1 (en) * 2002-03-29 2004-04-29 Azaya Therapeutics Inc. Novel formulations of digitalis glycosides for treating cell-proliferative and other diseases
US20140187505A1 (en) * 2002-05-28 2014-07-03 Bette Pollard Cardiac Glycosides to Treat Cystic Fibrosis and Other IL-8 Dependent Disorders
US20060041109A1 (en) * 2004-06-24 2006-02-23 Wisconsin Alumni Research Foundation Neoglycorandomization and digitoxin analogs

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
RANA ET AL.: "Ouabain inhibits placental sFlt1 production by repressing HSP27-dependent HIF-1a pathway", THE FASEB JOURNAL, vol. 28, no. 10, 26 June 2014 (2014-06-26), pages 4324 - 4334, XP055764174 *
YAKISICH ET AL.: "Chemoresistance of Lung and Breast Cancer Cells Growing Under Prolonged Periods of Serum Starvation", JOURNAL OF CELLULAR PHYSIOLOGY, vol. 232, no. 8, 9 August 2016 (2016-08-09), pages 2033 - 2043, XP055764361, DOI: 10.1002/jcp.25514 *

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