CN113194934A - Methods of treating solid tumor cancers using cryptobrevicin and biomarkers - Google Patents

Methods of treating solid tumor cancers using cryptobrevicin and biomarkers Download PDF

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CN113194934A
CN113194934A CN201980067429.3A CN201980067429A CN113194934A CN 113194934 A CN113194934 A CN 113194934A CN 201980067429 A CN201980067429 A CN 201980067429A CN 113194934 A CN113194934 A CN 113194934A
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阿迪蒂亚·库尔卡米
尤瓦内什·韦达拉朱
乌梅什·卡萨德
阿伦·阿塞萨比
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Abstract

Disclosed herein are methods for determining the likelihood that an individual afflicted with a solid tumor cancer will benefit from treatment with a cryptoleptin. In addition, there are also treatment methods based on such determinations. In several embodiments, the markers prostaglandin reductase 1(PTGR1), protein tyrosine phosphatase non-receptor 14 (PTPN14), aspartate beta-hydroxylase (ASPH), together or alone, may be used to enhance or direct treatment with cryptobrecin. In certain embodiments, the protein or gene may be expressed or methylated.

Description

Methods of treating solid tumor cancers using cryptobrevicin and biomarkers
Cross Reference to Related Applications
This application claims the benefit of U.S. provisional patent application No. 62/745,382 filed on 14/10/2018, which is incorporated herein by reference in its entirety.
Technical Field
The present invention relates to one or more markers for determining the sensitivity of a cancer patient to an anti-cancer agent (e.g., cryptoleptin) to be administered thereto, which markers can determine whether the patient's cancer has a therapeutic response to the application of the anti-cancer agent and the markers.
Background
Cryptoleptins have been chemically modified and used for the treatment of cancer. Iloufen (irofluven), a cryptobrevicin, is a chemically modified form of the mycotoxin cryptobrevicin S. It is a DNA alkylating agent with an abnormal mechanism. This cryptobrecin is a DNA and protein damaging agent targeting rapidly dividing malignant tumor cells. It enters tumor cells where it interferes with DNA replication and cell division by binding to DNA and protein targets. This results in the tumor cells shutting down and thus dying (apoptosis). One study determined that at certain doses, tumor cells were very susceptible to the dual destructive activity of iloufen, while normal cells showed only marginal response to cytocidal drugs. Not all solid cancers are sensitive to cryptobrevicin and methods to identify individuals sensitive to cryptobrevicin are elusive.
Despite recent advances in diagnostic and therapeutic strategies for individuals with solid tumors, particularly prostate, ovarian, liver and renal cancers, there remains a significant key knowledge gap in their screening and treatment. There is insufficient knowledge of patient characteristics (including genetic characteristics) with respect to optimally classifying individuals into response groups at the time of diagnosis. Knowledge of these risk factors for cancer development or death is also inadequate, and there is a lack of effective application of real world evidence in clinical practice. This lack of knowledge means that it is suboptimal to predict which individuals will have the best results under a particular treatment. In addition, current predictions as to which individuals may be harmed by unnecessary or inappropriate treatment or safely managed without treatment remain poor.
Thus, there is a need for a method for treatment and determining whether an individual will or is more or less likely to respond to treatment with cryptoleptin. The present application addresses this need among others.
Disclosure of Invention
The present application relates to methods for determining the likelihood that an individual suffering from a solid tumor cancer will benefit from treatment with a cryptoleptin. In addition, there are treatment methods based on such determinations. In several embodiments, the markers prostaglandin reductase 1(PTGR1), protein tyrosine phosphatase non-receptor type 14 (PTPN14), aspartate beta-hydroxylase (ASPH) are used in the methods together with or separately from one or more genes. In certain embodiments, the protein or gene may be expressed or methylated.
A method of treating a solid tumor cancer with targeted drug therapy, comprising:
identifying a patient having a cancer susceptible to treatment with a compound of the formula:
Figure BDA0003017261840000021
wherein R1, R2, and R3 are independently (C1-C4) alkyl, methyl, or hydroxy.
Definition of
The term "subject" refers to an animal, including but not limited to a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein, for example to refer to a mammalian subject, such as a human subject, in one embodiment a human.
The term "treating" is intended to include alleviating or eliminating a condition, or one or more symptoms associated with a condition; or to alleviate or eradicate the cause of the condition itself.
The term "managing" encompasses preventing recurrence of a given disease, disorder, or condition in a patient already suffering from the disease, disorder, or condition, and/or extending the time a patient suffering from the disease, disorder, or condition remains in remission. The terms encompass modulating the threshold, progression and/or duration of a disease, disorder or condition, or altering the way a patient responds to a disease, disorder or condition.
The term "preventing" is intended to include delaying and/or arresting the onset of a disorder, disease or condition and/or its attendant symptoms; prohibiting the subject from suffering from the disorder, disease, or condition; or reducing the risk of acquiring a disorder, disease, or condition in a subject.
The term "sensitivity" or "sensitivity" when referring to treatment with a compound is a relative term that refers to the degree of effectiveness of the compound in reducing or diminishing the progression of the disease, disorder, or condition being treated. For example, the terms "increased sensitivity" or "sensitivity to treatment" when used in relation to the treatment of a disease, disorder, or condition associated with a compound, refer to an increase in the effectiveness of the treatment of at least 3%, specifically at least 5%, or more.
As used herein, and unless otherwise specified, the term "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the presence of a disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment or management of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease, disorder, or condition, or enhances the therapeutic efficacy of another therapeutic agent.
As used herein, "effective patient response" refers to any increase in the therapeutic benefit to a patient. An "effective patient response" can be, for example, a 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% reduction in the rate of progression of the disease, disorder, or condition. An "effective patient response" can be, for example, a 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% reduction in physical symptoms of a disease, disorder, or condition. An "effective patient response" can also be, for example, an increase in a patient's response of 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 75%, 80%, 90%, 100%, 120%, 140%, 150%, 170%, 180%, 190%, 200% or more, as measured by any suitable method, such as gene expression, cell count, assay results, and the like.
An improvement in a disease, disorder, or condition can be characterized as a complete or partial response. By "complete response" is meant the absence of a clinically detectable disease with any prior abnormal radiographic studies, normalization of bone marrow and cerebrospinal fluid (CSF) or abnormal monoclonal protein measurements. By "partial response" is meant that all measurable disease, disorder, or condition burden (i.e., the number of malignant cells present in an individual, or the volume of a measured tumor mass or the amount of abnormal monoclonal protein) is reduced by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% in the absence of a new lesion. The term "treatment" encompasses both complete and partial responses.
The term "refractory or resistant" refers to a condition in which a patient does not respond to treatment even after intensive therapy. For example, a patient may have residual cancer cells (e.g., leukemia or lymphoma cells) in their lymphatic system, blood, and/or blood-forming tissues (e.g., bone marrow).
The terms "determining," "measuring," "evaluating," "assessing," and "analyzing," as used herein, generally refer to any form of measurement and include determining whether an element is present. These terms include quantitative and/or qualitative determinations. The evaluation may be relative or absolute. "assessing the presence of" can include determining the amount of something present, as well as determining whether it is present.
The terms "isolated" and "purified" refer to the separation of a substance (e.g., DNA/mRNA or protein) such that the substance makes up a substantial portion of the sample in which it resides, i.e., is larger than the substance normally found in its native or non-isolated state. Typically, a substantial portion of the sample comprises, for example, greater than 1%, greater than 2%, greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 40%, greater than 50%, or more, typically up to about 90-100% of the sample. For example, a sample of isolated DNA/mRNA may typically comprise at least about 1% total mRNA. Techniques for purifying polynucleotides are well known in the art and include, for example, gel electrophoresis, ion exchange chromatography, affinity chromatography, flow sorting, and sedimentation by density.
The term "sample" as used herein relates to a material or mixture of materials, typically but not necessarily in fluid form, that contains one or more components of interest.
As used herein, "biological sample" refers to a sample obtained from a biological subject, including samples of biological tissue or fluid origin obtained, reached or collected in vivo or in situ. Biological samples also include samples from regions of a biological subject containing pre-cancerous or cancerous cells or tissues. Such samples may be, but are not limited to, organs, tissues, fractions and cells isolated from mammals. Exemplary biological samples include, but are not limited to, cell lysates, cell cultures, cell lines, tissues, oral tissues, gastrointestinal tissues, organs, organelles, biological fluids, blood samples, urine samples, skin samples, and the like. Biological samples include, but are not limited to, whole blood, partially purified blood, PBMCs, tissue biopsies, and the like.
As used herein, and unless otherwise indicated, the term "optically pure" means a composition that comprises one optical isomer of a compound and is substantially free of the other isomer of the compound. For example, an optically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. An optically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound. Typical optically pure compounds contain greater than about 80% by weight of one enantiomer of the compound and less than about 20% by weight of the other enantiomer of the compound, or greater than about 90% by weight of one enantiomer of the compound and less than about 10% by weight of the other enantiomer of the compound, or greater than about 95% by weight of one enantiomer of the compound and less than about 5% by weight of the other enantiomer of the compound, or greater than about 97% by weight of one enantiomer of the compound and less than about 3% by weight of the other enantiomer of the compound, or greater than about 99% by weight of one enantiomer of the compound and less than about 1% by weight of the other enantiomer of the compound.
As used herein, the term "cryptoleptin" includes compounds having the formula I:
(I)
Figure BDA0003017261840000041
R1、R2and R3Independently (C1-C4) alkyl, methyl or hydroxy. The term cryptoleptins may include hydroxymethylacylfulvenes (HMAF, iloufen), having the following formula II:
(II)
Figure BDA0003017261840000042
the term cryptobrevicin may also include (-) -hydroxyurenomethylacylfulvene having the following formula III
(III)
Figure BDA0003017261840000051
Detailed Description
One member of the marker for determining sensitivity to anticancer agents includes the gene markers prostaglandin reductase 1(PTGR1), protein tyrosine phosphatase non-receptor 14 type (PTPN14), aspartate beta-hydroxylase (ASPH), together with or alone with one or more genes. In certain embodiments, a protein gene may be expressed or methylated. Prostaglandin reductase 1(PTGR1) is a highly inducible enzyme with enone reductase activity. The marker PTGRI is associated with sensitivity to cryptobrevicin-based therapy or with true responders to cryptobrevicin-based therapy. By developing predictive biomarker-based screening tests to enable accurate drug-based treatment of patients, the use of markers alone or in combination with other markers can reduce the gap in cancer (e.g., prostate cancer) treatment. The present inventors have found that detection of circulating solid tumor-associated mutant nucleic acid or protein sequences in an individual with solid tumor cancer can accurately determine whether the individual is susceptible to treatment with cryptoleptin.
In a specific embodiment, the DNA of PTGR1, PTPN14, ASPH genes are methylated. DNA methylation is the process of adding a methyl group to a DNA molecule. Methylation can alter the activity of a DNA fragment without altering the sequence. When located in a gene promoter, DNA methylation is often used to inhibit gene transcription.
A method for treating or managing solid tumor cancers (such as prostate, ovarian, liver, kidney and thyroid cancer) comprises
Identifying a patient having a cancer that is susceptible to treatment with: an anseracin of the formula:
Figure BDA0003017261840000052
cryptoleptin or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; and administering a therapeutically effective amount of a cryptoleptin to the patient.
A method of treating or managing a solid tumor comprises
Identifying a patient having a solid tumor cancer that is susceptible to treatment with: an anseracin having the formula:
Figure BDA0003017261840000061
or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; and
administering to the patient a therapeutically effective amount of a compound.
A method for predicting the response to treatment of a patient having a solid tumor, comprising:
obtaining a biological sample from the patient;
measuring the expression level of PTGR1, PTPN14, ASPH, or a combination thereof in the biological sample; and
comparing the expression level in the biological sample to the expression level of a biological sample from an individual not suffering from a solid cancer;
wherein an increased level of expression in the biological sample from the patient relative to an individual not having the solid tumor indicates a likelihood of an effective response to treatment with: a compound of the formula:
Figure BDA0003017261840000062
or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
A method for predicting the response to treatment of a patient having a solid tumor, comprising:
obtaining a biological sample from the patient;
measuring the expression level of PTGR1, PTPN14, ASPH, or a combination thereof in the biological sample; and
comparing the expression level of PTGR1, PTPN14, ASPH, or a combination thereof in the biological sample to the expression level of a biological sample from an individual not having a solid tumor;
wherein a decreased expression level of PTGR1, PTPN14, ASPH, or a combination thereof in a biological sample from the patient relative to an individual not having the solid tumor indicates a likelihood of having an effective response to treatment with: a compound of the formula:
Figure BDA0003017261840000071
or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
In one embodiment, provided herein is a method of treating or managing a solid tumor cancer comprising: identifying a patient having a solid tumor cancer susceptible to treatment with cryptoleptin or a pharmaceutically acceptable salt; and administering to the patient a therapeutically effective amount of the compound. In certain embodiments, the methods provided herein further comprise administering a therapeutically effective amount of an additional active agent that is a cryptoleptine.
In one embodiment, the cryptosporidium is administered once on day 1 of a 21 day cycle or another cycle.
In another embodiment, the cryptoleptin may be administered together with one or more second active ingredients. Such active ingredients may be other anti-cancer agents or agents used to treat cancer patients.
As stated above, solid tumor cancers may be selected from the group consisting of: colorectal cancer, pancreatic cancer, primary liver cancer, renal cancer, ovarian cancer, uterine cancer, lung cancer, breast cancer, prostate cancer, sarcoma, and adipose tissue cancer.
In one embodiment, one or more of the following genes may be used with PTGR1 as markers for determining sensitivity to cryptobrecin-based anticancer agents: TNFRSF1B, LCK, TAL1, GNG12, S100A10, CD247, ATP1B1, LAMC1, PTPRC, PTPN7, PTPN14, CAPN2, ENAH, LCT, CXCR4, ITGA4, CASP 10, HDAC4, NUP210, WWTR 4, PFN 4, MLF 4, CD 4, RHOH, ITK, LCP 4, HIST1H3 4, MYB, IKFZF 4, PIK3 4, MET, NRF 4, TRBC 4, PTPRN 4, PTK 24, ASPH, CNTRL, PRKCQ, MYOF, CTBP 4, LMO 4, CD3 4, KAF 4, NCKAP 14, NCCKAP 4, TFCL 4, LCP 72, CTTLC 4, ATCLTFFA, TFSC 4, ATCGI 4, TFFA 4, TFSC 4, TFS 4, WW 4, TFA 4, TFS 4, WW 4, TFS 4, and WW 4, TFS 4, and WW 4.
In another embodiment, one or more of the following gene markers may be used: WWTR1, HIST1H3B, ASPH, MYOF, CTBP2, CBFA2T3, and SDC 4. In another embodiment, one or more markers are combined with PTGR1, and one, more, or all of the following genes are combined with PTGR 1: PTPN14, ITGA4, HDAC4, ITK, IKZF1, PIK3CG, NRF1, ASPH and PRKCQ. In some cases, the sensitivity may approach 100%.
In another embodiment, two markers PTGR1 and SDC4 may be used as markers.
In the case of using the PTGR1 gene combination, screening for an anticancer drug susceptibility enhancer can be performed by using, as an index, the change in expression of the PTGR1 gene combination after exposure to a cryptoleptin-based anticancer agent. That is, decreasing the level of PTGR1 gene combination prior to exposure to a cryptobrecin-based anticancer agent, or promoting expression changes or elevated levels of a substance after in vitro or in vivo exposure to a cryptobrecin-based anticancer agent enhances sensitivity to the anticancer agent. In addition, in the in vitro case, a substance that promotes an expression change or elevated level upon exposure to an anticancer agent corresponding to a target cancer cell may be used as a substance that enhances sensitivity to a cryptoleptin-based anticancer agent (i.e., an anticancer agent sensitivity enhancer).
To perform a method of determining the susceptibility of a sample to an anti-cancer agent, a kit containing a protocol for measuring any substance present in the sample is employed. The kit contains a reagent for measuring any of these substances, instructions of an instruction manual for using the reagent, a standard for determining the presence or absence of sensitivity to a cryptoleptin-based anticancer agent, and the like. The criteria include (relative) standard levels of these metabolic-related substances, (relative) high threshold levels, (relative) low threshold levels, factors affecting the measurement, degree of influence, and the like. These levels of material may be set to correspond to the selected cryptosporine-based anti-cancer agent. The sensitivity determination may be performed in the same manner based on criteria.
Screening of the cryptosporidium-based anticancer agent may be performed by means of the cryptosporidium-based anticancer agent sensitivity determination marker as an index. That is, a substance that can change the level of an anticancer agent sensitivity determination marker in vitro or in vivo is evaluated as an anticancer agent. For example, in an in vitro situation, a substance that alters the levels of an anti-cancer agent sensitivity-determining marker in various cancer cells after exposure to the substance may serve as an anti-cancer agent. In addition, a substance may act as an anticancer agent when its anticancer agent sensitivity-determining marker level is changed after administration of the substance to an animal carrying cancer. If the anticancer agent is expected to exhibit a pharmacological effect, an increase in the level of the anticancer agent sensitivity-determining marker is observed before tumor shrinkage occurs or a cytocidal effect is achieved. Therefore, screening based on determination of a marker level as an index for sensitivity to an anticancer agent can achieve determination of whether a test substance acts as an applicable anticancer agent in a shorter period of time, whereby efforts and costs involved in development of an anticancer agent are greatly expected to be reduced.
When the cancer has no sensitivity to the anticancer agent, any pharmacological effect cannot be expected from the anticancer agent. If such a non-potent anticancer agent is continuously administered to a patient, cancer may progress and side effects may be aggravated. Therefore, the anticancer agent sensitivity determination marker can be used not only to determine the therapeutic response to an anticancer agent but also greatly contribute to preventing exacerbation of side effects which would otherwise be caused by continuous administration of an anticancer agent having no pharmaceutical activity.
By using the thus obtained anticancer agent sensitivity enhancer and the cryptomerin-based anticancer agent as the sensitivity enhancement target of the enhancer in a combined manner, the therapeutic effect of the cryptomerin-based anticancer agent is greatly enhanced. The combination of the cryptoleptin-based anticancer agent sensitivity enhancer and the anticancer agent as the sensitivity enhancing target of the enhancer may be a composition containing two components, or a combination drug containing preparations of individual components.
To assist in monitoring the individual, particularly if the reference value is obtained from the individual, as part of an ongoing screening procedure. Alternatively, the reference value may be obtained from a population of individuals not suffering from solid tumor cancer.
Cells for testing may be obtained by any method known in the art, including but not limited to surgical resection; biopsies such as, but not limited to, needle biopsies, core biopsies, or aspirations; or collected from a fluid sample, such as blood, urine, cerebrospinal fluid, cystic fluid, and the like. Methods for measuring DNA/mRNA include, but are not limited to, polymerase chain reaction, in situ hybridization, gel electrophoresis, sequence analysis, and microarray analysis, or combinations thereof. Methods for measuring proteins include, but are not limited to, mass spectrometry, 1-D or 2-D gel-based assay systems, chromatography, enzyme-linked immunosorbent assay (ELISA), Radioimmunoassay (RIA), Enzyme Immunoassay (EIA), Western blotting, immunoprecipitation, and immunohistochemistry. Antibody arrays or protein chips may also be used. An agent "likely" to produce an anti-cancer effect in an individual means that the individual is more similar to other individuals in whom the agent produces a significant anti-cancer effect than other individuals in whom the agent does not produce a significant anti-cancer effect in one or more of the parameters tested (e.g., the amount of PTGR1, PTPN14, and ASPH mRNA, the amount of methylated DNA and/or protein, the expression levels of genes or exons listed in example 1). An agent "unlikely" to produce an anti-cancer effect in an individual means that the individual is more similar to other individuals in whom the agent does not produce a significant anti-cancer effect than to other individuals in which the agent produces a significant anti-cancer effect in the one or more parameters tested.
The pharmaceutical compositions may be used to prepare individual single unit dosage forms. Pharmaceutical compositions and dosage forms provided herein comprise an immunomodulatory compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or prodrug thereof. The pharmaceutical compositions and dosage forms provided herein can further comprise one or more excipients.
The pharmaceutical compositions and dosage forms provided herein may further comprise one or more second active ingredients. Accordingly, the pharmaceutical compositions and dosage forms provided herein comprise an active ingredient (e.g., an immunomodulatory compound) disclosed herein. Examples of optional second or additional active ingredients are disclosed herein.
Also encompassed are kits and compositions for performing the methods provided herein. In certain embodiments, provided herein are kits suitable for determining the efficacy of an anti-cancer compound. In certain embodiments, provided herein are kits useful for assessing the efficacy of a compound in treating a patient. In some embodiments, provided herein are kits suitable for determining the effect of an immunomodulatory compound. The kit comprises a solid support and means for detecting gene, protein or glycoprotein expression of at least one biomarker in a biological sample. Such kits may employ, for example, dipsticks, membranes, chips, discs, test strips, filters, microspheres, slides, multiwell plates, or optical fibers. The solid support of the kit can be, for example, plastic, silicon, metal, resin, glass, membrane, particle, precipitate, gel, polymer, flake, sphere, polysaccharide, capillary, film, plate, or slide. The biological sample may be, for example, a cell culture, a cell line, a tissue, an oral tissue, a gastrointestinal tissue, an organ, an organelle, a biological fluid, a blood sample, a urine sample, or a skin sample.
In one embodiment, the kit provided herein comprises a cryptoleptin compound provided herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof. The kit may further comprise additional active agents, including but not limited to those disclosed herein.
Examples of the invention
Certain embodiments provided herein are illustrated by the following non-limiting examples. As shown in example 1, analysis of in vitro cryptoleptin (LP-184) sensitivity data from a panel of cancer cell lines with known multiomic molecular profiles yielded signatures of 10 genes (ASPH, HDAC4, IKZF1, ITGA4, ITK, NRF1, PIK3CG, PRKCQ, PTGR1, and PTPN14) that were able to predict cryptoleptin sensitivity with up to or including 100% accuracy in blind tests. The gene expression, DNA mutation, DNA methylation and protein expression status of these 10 genes were further calculated as a correlation with cryptoleptin (LP-184) sensitivity. As shown in table 1, of these 10 genes, 3 genes appeared to have a highly significant correlation with the cryptoleptine bioactivity at the multigenomic level. These genes are identified as PTGR1, PTPN14, and ASPH. These 3 genes also have the highest gene weights in terms of relative importance when determining the cryptoleptine (LP-184) sensitivity according to FIG. 1. As shown in fig. 2, it is presented as the most prominent gene in classifying the samples as cryptoleptin responders or non-responders. In general, a novel gene set has been established to determine sensitivity to and predict response to cryptoleptins (LP-184) in cancer.
Example 1
Genes associated with LP-184 (cryptoleptin family) sensitivity in cancer
Figure BDA0003017261840000101
FIG. 1 shows the relative importance of exemplary gene signatures to hydroxyurea methylacyl fulvene. In this relative variable significance map, a gene weight analysis was performed to analyze the relative ranking of the top 10 genes in the hydroxyurea methyloyl fulvene signature in cancer. The data show that PTGR1 (prostaglandin reductase 1) followed by PTPN14 and ASPH are gene signatures of hydroxyurea methyl acyl fulvene sensitivity.
Fig. 2 shows that PTGR1 and PTPN14 are associated with positive reactions against hydroxyurea methylacyl fulvene. In this sensitivity analysis plot, the effect of gene expression on response variables was studied across the LP-184 gene signature using the lekprofile function. High expression of PTGR1 (prostaglandin reductase 1) was associated with a positive response to LP-184), with PTPN14 being the next most highly related gene. This experiment was performed on a panel of cancer cells.
The embodiments described above are intended to be exemplary only, and those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the embodiments and are encompassed by the following claims.

Claims (19)

1. A method of treating a solid tumor cancer with a targeted drug therapy comprising identifying a patient having a cancer susceptible to treatment with a compound of the formula:
Figure FDA0003017261830000011
wherein R1, R2, and R3 are independently (C1-C4) alkyl, methyl, or hydroxy.
2. The method of claim 1, further comprising the step of measuring the expression level of PTGR1 of its combination in a biological sample.
3. The method of claim 1, further comprising the step of measuring the expression level of PTPN14 in the biological sample.
4. The method of claim 1, further comprising the step of measuring the expression level of ASPH in the biological sample.
5. The method of claim 1, wherein the cancer is newly diagnosed, relapsed, or refractory.
6. The method of claim 1, further comprising modifying targeted drug therapy based on expression of a gene.
7. The method of claim 2, wherein PTGR1, PTPN14, or ASPH is methylated.
8. The method of claim 1, wherein the cryptoleptin has the structure:
Figure FDA0003017261830000012
9. the method of claim 1, wherein the cancer is colorectal cancer, pancreatic cancer, primary liver cancer, renal cancer, ovarian cancer, uterine cancer, lung cancer, breast cancer, prostate cancer, sarcoma, or adipose tissue cancer.
10. A method of treating or managing a solid tumor treatment, comprising:
identifying a patient having a solid tumor cancer that is susceptible to treatment with: an anseracin having the formula:
Figure FDA0003017261830000021
or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; and
administering to the patient a therapeutically effective amount of a cryptoleptin.
11. The method of claim 10, wherein the biological sample is blood, plasma, serum, or tissue biopsy.
12. The method of claim 11, further comprising the step of measuring the expression level of PTGR1 in the biological sample.
13. The method of claim 12, further comprising the step of measuring the expression level of PTPN14 in the biological sample.
14. The method of claim 12, further comprising the step of measuring the expression level of ASPH in the biological sample.
15. A method for predicting the response to treatment of a patient having a solid tumor, comprising:
obtaining a biological sample from the patient;
measuring the expression level of PTGR1, PTPN14, ASPH, or a combination thereof in the biological sample; and
comparing the expression level in the biological sample to an expression level of a biological sample from an individual not having a solid cancer;
wherein an increase in the expression level in the biological sample from the patient relative to the individual not having the solid tumor indicates a likelihood of an effective response to treatment with: a compound of the formula:
Figure FDA0003017261830000022
or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
16. A kit for determining whether it is likely to produce an anti-cancer effect in a cancer by cryptobrecin, comprising means for determining the level of expression in a cancer relative to the level of expression of PTGR1, PTPN14, ASPH or a combination thereof from an individual having a solid tumor relative to normal values of a biological sample from a patient.
17. The method of claim 16, wherein the cancer is colorectal cancer, pancreatic cancer, primary liver cancer, renal cancer, ovarian cancer, uterine cancer, lung cancer, breast cancer, prostate cancer, sarcoma, or adipose tissue cancer.
18. A kit for determining whether it is likely to produce an anti-cancer effect in a cancer by cryptobrecin, comprising means for determining the level of mRNA, DNA and/or protein corresponding to PTGR1, PTPN14, ASPH or a combination thereof in one or more cells of the cancer.
19. The kit of claim 16 or 18, wherein the cryptomerin has
Figure FDA0003017261830000031
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