JP2022513349A - Treatment of solid tumor cancer using ildin and biomarkers - Google Patents

Abstract

Disclosed herein are methods of determining the likelihood that a subject suffering from solid tumor cancer will benefit from treatment with ildin. Further, a treatment method based on the determination is also disclosed. In some embodiments, the markers Prostaglandin redutase 1 (PTGR1), Protein Tyrosine Phosphatase Non-Receptor Type 14 (PTPN14), Aspartate Beta-Hydroxylase (ASP) alone, with Beta-Hydroxylase (ASP)) It may be used to enhance or induce the treatment used. In certain embodiments, the protein or gene may be expressed or methylated.

Description

Cross-references to related applications This application claims the benefit of US Provisional Patent Application No. 62 / 745,382 filed October 14, 2018, which is herein in its entirety. Incorporated by reference to.

The present invention relates to a marker for use in determining the susceptibility of a cancer patient to an anticancer agent (eg, illudins) administered to the cancer patient, and an application of the marker, wherein the marker is the cancer patient. Can be determined to have therapeutic responsiveness to the anticancer drug.

Illudin is chemically modified and used in the treatment of cancer. The ildin, Irofulven, is a chemically modified form of the mycotoxin ildin S. Irofulven is a DNA alkylating agent and has a unique mechanism. This ildin is a DNA and protein damaging agent that targets rapidly dividing malignant tumor cells. Irofulven enters tumor cells and interferes with DNA replication and cell division by binding to DNA and protein targets. As a result, the tumor cells become arrested and die (apoptosis). Studies have shown that at certain doses tumor cells are highly sensitive to the double-damaging activity of irofulven, while normal cells show a modest response to this cell-killing agent. Not all solid tumors are vulnerable to illudin, and methods for determining illudin-sensitive subjects have been difficult.

Despite the recent developments in diagnostic and therapeutic strategies, especially for patients with solid tumors such as prostate, ovarian, liver and kidney cancer, there are many significant knowledge gaps regarding screening and treatment. Knowledge of patient characteristics, including genetic profiles, for optimal stratification of subjects into responsive groups at the time of diagnosis is inadequate. In addition, knowledge of the risk factors for developing these cancers or dying from these cancers is inadequate, and there is also a lack of effective introduction of real-world evidence into clinical practice. This lack of knowledge means that predictions of which subjects have the best outcomes for a particular treatment have not been optimized. In addition, there are few current predictions as to which subjects may be harmed by unnecessary or inappropriate treatment, or may be successfully managed without treatment. There is up to.

Therefore, there is a need for a method of treatment and a method of determining whether a subject is responsive to illudin treatment or may be more or less responsive. It is this need that is particularly aimed at in this application.

The present application relates to a method for determining the likelihood that a subject suffering from solid tumor cancer will benefit from treatment with ildin. Further, it also relates to a treatment method based on the determination. In some embodiments, the markers Prostaglandin redutase 1 (PTGR1), Protein Tyrosine Phosphatase Non-Receptor Type 14 (PTPN14), Aspartate Beta-Hydroxylase (ASP) alone, one gene, one gene, one or more, and one gene (ASP) alone. Used in. In certain embodiments, the protein or gene may be expressed or methylated.

How to treat solid tumor cancer with targeted drug therapy
The following formula:

Including identifying patients with cancer who are sensitive to treatment with the compounds of
In the formula, R1, R2 and R3 are independently (C1-C4) alkyl, methyl or hydroxyl.

Definitions The term "subject" refers to animals, including, but not limited to, primates (eg, humans), cows, pigs, sheep, goats, horses, dogs, cats, rabbits, rats or mice. The terms "subject" and "patient" are used interchangeably herein in the context of, for example, a human subject and, in one embodiment, a mammalian subject such as a human.

The terms "treat," "treat," and "treat" alleviate or eliminate one or more of the condition or symptoms associated with the condition, or alleviate the cause of the condition itself. It is intended to include that, or eradication.

The terms "manage," "manage," and "manage" are used to prevent the recurrence of a particular disease, disorder, or condition in a patient who is already suffering from that disease, disorder, or condition, and / Or it includes prolonging the time a patient suffering from the disease, disorder or condition stays in remission. The term includes adjusting the threshold, development and / or duration of the disease, disorder or condition, or changing the situation in which a patient responds to the disease, disorder or condition.

The terms "prevent," "prevent," and "prevention" are methods, subjects that delay and / or do not cause an injury, disease or condition, or associated symptoms. It is intended to include methods to prevent this from happening, or to reduce the risk of an injury, illness, or condition subject.

The terms "susceptibility" and "susceptibility" associated with treatment with a compound refer to the degree of effectiveness of the compound in reducing or reducing the progression of the disease, disorder or condition being treated. It is a relative term. For example, the terms "increased susceptibility" or "susceptible to treatment" when used in connection with the treatment of a disease, injury or condition associated with a compound, at least 3%, in particular at least 5% or more. Refers to an increase in therapeutic efficacy.

As used herein, and unless otherwise specified, the term "therapeutically effective amount" of a compound is an amount sufficient to provide therapeutic benefit in the treatment or management of a disease, injury or condition. Or an amount sufficient to delay or minimize one or more symptoms associated with the presence of a disease, disorder or condition. The therapeutically effective amount of a compound means the amount of a single therapeutic agent or the amount of a therapeutic agent used in combination with another therapeutic agent that provides therapeutic benefit in the treatment or management of a disease, disorder or condition. The term "therapeutically effective amount" includes an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease, injury or condition, or enhances the therapeutic efficacy of another therapeutic agent. obtain.

As used herein, "effective patient response" refers to any increase in therapeutic benefit to a patient. "Effective patient response" is, for example, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, in the rate of progression of a disease, disorder or condition. It can be a 45%, 50%, 60%, 70%, 75%, 80%, 90% or 100% reduction. "Effective patient response" is, for example, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% in the physical symptoms of a disease, disorder or condition. , 45%, 50%, 60%, 70%, 75%, 80%, 90% or 100% reduction. "Effective patient response" is 5%, 7.5%, 10%, 15% of a patient's response as measured by any suitable means, such as gene expression, cell count, analysis results, etc. , 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 75%, 80%, 90%, 100%, 120%, 140%, 150%, 170 It can be an increase of%, 180%, 190%, 200% or more.

Improvements in a disease, disorder or condition can be characterized as a complete or partial response. "Complete response" is the absence of clinically detectable disease with normalization of any past abnormal radiological examination, bone marrow and cerebrospinal fluid (CSF) or abnormal monoclonal protein measurements. Point to. "Partial response" is the load of any measurable disease, disorder or condition in the absence of new lesions (ie, the number of malignant cells present in the subject, or the measured volume of the tumor mass, or an abnormal monoclonal). Amount of protein) refers to a reduction of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. The term "treatment" expects both complete and partial responses.

The term "refractory or resistant" refers to a situation in which a patient does not respond to treatment, even after intensive care. For example, a patient may have residual cancer cells (eg, leukemia cells or lymphoma cells) in the lymphatic system, blood and / or blood-forming tissue (eg, bone marrow).

As used herein, the terms "determining," "measuring," "examining," "evaluating," and "analyzing" generally refer to any form of measurement. Includes determining the presence or absence of an element. These terms include both quantitative and / or qualitative judgments. The evaluation may be relative or absolute. "Evaluating the existence of ..." may include determining any quantity present, as well as determining existence or non-existence.

The terms "isolated" and "purified" refer to the isolation of a substance such that the substance constitutes the majority of the sample in which the substance (eg, DNA / mRNA or protein) is present. That is, it refers to isolating a substance so that it constitutes more than is typically present in its natural or non-isolated state. Typically, the majority of the sample is, for example, more than 1%, more than 2%, more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 40% of the sample. , 50% or more, usually 90% to 100% or less of the sample. For example, an isolated DNA / mRNA sample can typically contain at least about 1% total mRNA. Polynucleotide purification techniques are known in the art and include, for example, gel electrophoresis, ion exchange chromatography, affinity chromatography, flow sorting, and density-based precipitation.

As used herein, the term "sample" relates to a material or mixture of materials, typically in liquid form, but not necessarily, and contains one or more components of interest. do.

As used herein, "biological sample" refers to a sample taken from a biological subject, an organism taken in vivo or in situ, reached or collected. Includes samples of scientific tissue or liquid origin. Biological samples also include samples derived from regions of biological subject containing precancerous or cancerous cells or tissues. Such samples can be, but are not limited to, organs, tissues, fractions and cells isolated from mammals. Not limited to exemplary biological samples, cell lysates, cell cultures, cell lines, tissues, oral tissues, gastrointestinal tissues, organs, cell microorganisms, biological fluids, blood samples, urine samples, Examples include skin samples. 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" comprises one optical isomer of a compound and substantially no other isomers of that compound. Means a composition. For example, an optically pure composition of a compound having one chiral center is substantially free of enantiomers on the opposite side of the compound. The optically pure composition of a compound having two chiral centers is substantially free of other diastereomers of the compound. A typical optically pure compound comprises more than about 80% by weight of one mirror isomer of the compound and less than about 20% by weight of the other mirror isomers of the compound, or one of the compounds. More than about 90% by weight of the mirror image isomer and less than about 10% by weight of the other mirror image isomers of the compound, or more than about 95% by weight of one mirror image isomer of the compound, and the other of the compound. It contains less than about 5% by weight of the mirror image isomer, or more than about 97% by weight of one mirror image isomer of the compound, and less than about 3% by weight of the other mirror image isomers of the compound, or one of the compounds. It contains more than about 99% by weight of one mirror isomer and less than about 1% by weight of other mirror isomers of the compound.

As used herein, the term "illudin" is used in Formula I:

Includes compounds with.
R ₁ , R ₂ , and R ₃ are independently (C1-C4) alkyl, methyl, or hydroxyl. The term illudin may include hydroxymethylacylfulvene (HMAF, irofulven), the compound being of formula II:

Have.

The term illudin may include (-)-hydroxyureamethylacylfluvene ((-)-HydroxyUreaMethylAcylfulvene), the compound being of formula III:

Have.

FIG. 1 shows the relative importance of the exemplary gene signature of hydroxyureamethylacylfluven. Gene weighting analysis was performed on this relative variability importance graph to analyze the relative ranking of the top 10 genes in the hydroxyureamethylacylfluvene signature in cancer. The data show that PTGR1 (Prostaglandin reductase 1), followed by PTPN14 and ASPH, are the gene signatures for hydroxyureamethylacylfluben sensitivity. FIG. 2 shows the association between PTGR1 and PTPN14 with a positive response to hydroxyureamethylacylfluven. In this susceptibility analysis graph, the lekprofile function was used to validate the effect of gene expression on responsive variation across the LP-184 gene signature. High expression of PTGR1 (Prostaglandin reductase 1) correlated with a positive response to LP-184. PTPN14 was the runner-up highly correlated gene. This experiment was performed on a cancer cell panel.

The embodiments described above are intended to be merely exemplary, and one of ordinary skill in the art may recognize or confirm many equalities of a particular compound, material and procedure using experiments that do not go beyond routine. You can do it. All such equality is considered to be within the scope of the present embodiment and is included in the appended claims.

Members of one of the anti-cancer drug susceptibility determination markers include the gene markers Prostaglandin redictase 1 (PTGR1), Protein Tyrosine Phosphatase Non-Receptor Type14 (PTPN14), and AspN, which are gene markers used alone or in combination with one or more genes. (ASPH). In certain embodiments, the protein gene may be expressed or methylated. Prostaglandin redutase 1 (PTGR1) is a highly inducible enzyme with enone reductase activity. The marker PTGR1 correlated with susceptibility to illudin therapy or with a true responder to illudin therapy. Predictive biomarker-based screening tests have been developed that, when used alone or in combination with this marker, enable personalized care-based treatment of patients for cancer (eg, prostate). The gap in the treatment of cancer) can be reduced. We accurately determine whether the detection of a circulating, solid tumor-related mutant nucleic acid or protein sequence in a subject with solid tumor cancer is sensitive to treatment with ildin. I found it possible.

In certain embodiments, the DNA of the PTGR1, PTPN14, ASPH genes is methylated. DNA methylation is the process by which a methyl group is added to a DNA molecule. Methylation can alter the activity of DNA segments without altering the sequence. When positioned as a gene promoter, DNA methylation often acts to suppress gene transcription.

Treatment or management methods for solid tumor cancers (eg, prostate cancer, ovarian cancer, liver cancer, kidney cancer and thyroid cancer)
The following formula:

To identify patients with cancer who are sensitive to treatment with illdin, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and administer a therapeutically effective amount of the ildin to the patient. Including doing.

How to treat solid tumors or manage solid tumor treatment
The following formula:

Identifying a patient with solid tumor cancer who is sensitive to treatment with illdin, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and the therapeutic efficacy of the compound in the patient. Includes administration of dose.

A method of predicting treatment responsiveness in patients with solid tumors.
Obtaining a biological sample from the patient,
Measuring the expression levels of PTGR1, PTPN14, ASPH, or a combination thereof in the biological sample, and the expression levels in the biological sample, are biological samples from subjects without solid tumors. Including, comparing with the expression level of
The increase in expression levels in biological samples from the patient as compared to levels from subjects without solid tumors is as follows:

A method of demonstrating the potential for an effective response to treatment with a compound of or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

A method of predicting treatment responsiveness in patients with solid tumors.
Obtaining a biological sample from the patient,
Measuring the expression level of PTGR1, PTPN14, ASPH, or a combination thereof in the biological sample, and the expression level of PTGR1, PTPN14, ASPH, or a combination thereof in the biological sample, solid tumor. Comparing with the expression level of biological samples from subjects that do not have, including
The reduction in expression levels of PTGR1, PTPN14, ASPH, or a combination thereof in biological samples from the patient as compared to levels from subjects without solid tumors is as follows:

A method of demonstrating the potential for an effective response to treatment with a compound of or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

In one embodiment of the specification, identifying a patient with solid tumor cancer who is sensitive to treatment with ildin, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of the compound. Provided are methods of treating or managing solid tumor cancer, including administration to. In certain embodiments, there is provided a method herein further comprising administering a therapeutically effective amount of an additional active agent that is an illudin.

In one embodiment, the illudin is administered once on the first day of a 21-day cycle or another cycle.

In another embodiment, the illudin may be administered with one or more second active ingredients. Such active ingredients may be other anti-cancer agents or agents used in the treatment of cancer patients.

As mentioned above, solid tumor cancers are 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. May be good.

In one embodiment, one or more of the following genes may be used as markers with PTGR1 to determine susceptibility to illudin-based anticancer agents: TNFRSF1B, LCK, TAL1, GNG12, S100A10, CD247, ATP1B1, LAMC1, PTPRC, PTPN7, PTPN14, CAPN2, ENAH, LCT, CXCR4, ITGA4, CASP10, HDAC4, NUP210, WWTR1, PFN2, MLF1, CD38, RHOH, ITK, LCP2, HIST1H3B, NRF1, TRBC1, PTPRN2, PTK2B, ASPH, NFIB, CNTRL, PRKCQ, MYOF, CTBP2, LM02, CD3D, TWF1, NCKAP1L, CKAP4, LCP1, CFL2, TJP1, ALDH1A2, TLC3 ATP2A3, GIPC1, HAUS5, MAP4K1, SDC4, APP, SLC38A5, WAS, and IL2RG.

In another embodiment, one or more of the following genetic markers may be used: WWTR1, HIST1H3B, ASPH, MYOF, CTBP2, CBFA2T3, and SDC4. In another embodiment, one or more markers were combined with PTGR1 and one, more, or all of the following genes were combined with PTGR1: PTPN14, ITGA4, HDAC4, ITK, IKZF1, PIK3CG. , NRF1, ASPH, and PRKCQ. In some embodiments, susceptibility can approach 100%.

In yet another embodiment, two markers, PTGR1 and SDC4, may be used as markers.

When the PTGR1 gene combination is used, screening of anticancer drug susceptibility enhancers can be performed by adopting the variation in the expression of the PTGR1 gene combination after exposure to an illudin-based anticancer drug as an index. That is, in vitro or in vivo, a substance that reduces the PTGR1 gene combination level before exposure to an illudin anticancer drug, or a substance that promotes expression fluctuation, or a substance that raises the level after exposure to an illudin anticancer drug enhances sensitivity to the anticancer drug. In addition, in vitro, substances that promote variability in expression, or substances that increase levels after exposure to the corresponding anti-cancer drug corresponding to the target cancer cell, can serve as substances that enhance susceptibility to illudin-based anti-cancer drugs (ie). , Anti-cancer drug sensitivity enhancer).

To implement a method for determining the susceptibility of a sample to an anticancer drug, a kit containing a protocol for measuring any of the substances present in the sample is employed. The kit contains reagents for measuring any of these substances, labeling of instruction manuals for reagent use, standards for determining susceptibility to illudin-based anticancer agents, and the like. Standards include (relative) standard levels, (relative) high threshold levels, (relative) low threshold levels, factors influencing the measurement, and degree of effect of these metabolism-related substances. These substance levels may be set to suit the selected illudin anticancer agent. The susceptibility determination may be performed in the same manner based on the standard.

Screening for illudin-based anticancer agents can be performed using an illudin-based anticancer agent susceptibility determination marker as an index. That is, a substance capable of changing the level of the anticancer drug susceptibility determination marker in vitro or in vivo is judged as an anticancer drug. For example, in the case of in vitro, in various cancer cells, a substance that changes the level of an anticancer drug susceptibility determination marker after exposure to the substance can serve as an anticancer drug. Further, in a cancer-carrying animal, when the level of the anticancer drug susceptibility determination marker changes after administration of the substance to the animal, the substance can play a role as an anticancer drug. If the anti-cancer drug is expected to exhibit pharmacological effects, elevated levels of anti-cancer drug susceptibility determination markers are observed before the onset of tumor shrinkage or before the appearance of cell-killing effects. Therefore, screening based on the anti-cancer drug susceptibility determination marker level as an index can determine whether or not the test substance plays a role as a useful anti-cancer drug in a shorter period of time, and accordingly, the labor and cost required for developing the anti-cancer drug. Is expected to drop significantly.

If the cancer is not sensitive to the anti-cancer drug, no pharmacological effect can be expected from the anti-cancer drug. If such non-pharmaceutical anti-cancer drugs continue to be administered to patients, the cancer may progress and side effects may be exacerbated. Therefore, the anti-cancer drug susceptibility determination marker is not only adopted for determining the therapeutic response to the anti-cancer drug, but may also greatly contribute to the prevention of exacerbation of side effects caused by continuous administration of the anti-cancer drug having no pharmaceutical effect.

By adopting the anticancer drug sensitivity enhancer thus obtained in combination with the illudin-based anticancer drug which is the sensitivity enhancing target of the enhancer, the therapeutic effect of the illudin-based anticancer drug is dramatically improved. The combination of the illudin-based anticancer agent susceptibility enhancer and the anticancer agent which is the sensitivity enhancing target of the enhancer may be a composition containing both components, or may be a combination drug of a preparation containing individual components. ..

Subject monitoring is assisted, especially when reference values are obtained from the subject as part of an ongoing screening program. Alternatively, the reference value may be obtained from a target population that does not have solid tumor cancer.

Validating cells include, but are not limited to, during surgical resection, but not limited to needle biopsy, core biopsy, or biopsy such as aspiration, or, for example, blood, urine, cerebrospinal fluid, cystic fluid, etc. It may be obtained by any method known in the art, including collection from liquid samples of. 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 a combination thereof. The method for measuring protein is not limited to mass spectrometry, 1-D or 2-D gel analysis system, chromatography, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), enzyme. Immunoanalysis (EIA), Western blotting, immunoprecipitation, and immunohistochemistry include. Antibody arrays or protein chips may be employed. In a subject, "probably" that the agent produces an anti-cancer effect is listed in the parameters validated (eg, PTGR1, PTPN14, and ASPH mRNA, methylated DNA and / or protein, Example 1). In (such as the level of expression of the gene or exon), the subject is more similar to other subjects to which the agent produces significant anticancer effects than to other subjects to which the agent does not produce significant anticancer effects. It means that you are doing. In a subject, "less likely" that the agent produces an anti-cancer effect is that the agent is more prominent than other subjects in which the agent produces a significant anti-cancer effect in the parameters being validated. It means that it is more similar to other subjects that do not produce anti-cancer effects.

The pharmaceutical composition can be used as an individual single unit dosage form formulation. The pharmaceutical compositions and dosage forms provided herein are immunomodulatory compounds provided herein, or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, or steric isomers thereof. Includes prodrugs. The pharmaceutical compositions and dosage forms provided herein may further comprise one or more excipients.

The pharmaceutical compositions and dosage forms provided herein may also include one or more second active ingredients. As a result, the pharmaceutical compositions and dosage forms provided herein include the active ingredients disclosed herein (eg, immunomodulatory compounds). Examples of the optimal second active ingredient or additional active ingredient are disclosed herein.

Kits and compositions for carrying out the methods provided herein are also expected. In certain embodiments, kits are provided herein that are useful in determining the efficacy of anti-cancer compounds. In certain embodiments, the present specification provides a kit useful for analyzing the efficacy of a compound in treating a patient. In some embodiments, kits useful herein are provided to determine the effect of immunomodulatory compounds. The kit includes a solid support and means for detecting the expression of at least one biomarker gene, protein or glycoprotein in a biological sample. Such kits may employ, for example, urine test strips, membranes, chips, discs, test strips, filters, microspheres, slides, multiwell plates, or optical fibers. The solid support of the kit may be, for example, plastic, silicon, metal, resin, glass, membrane, particle, precipitate, gel, polymer, sheet, sphere, polysaccharide, capillary, film, plate or slide. The biological sample may be, for example, a cell culture, cell line, tissue, oral tissue, gastrointestinal tissue, organ, intracellular small organ, biological fluid, blood sample, urine sample, or skin sample. ..

In one embodiment, the kits provided herein comprise an illudin compound provided herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. The kit may further include additional activators, such as, but not limited to, the activators disclosed herein.

Certain embodiments provided herein are described by the following non-limiting examples.

As shown in Example 1, 10 genes (ASPH, HDAC4, IKZF1, IKZF1, The signatures of ITGA4, ITK, NRF1, PIK3CG, PRKCQ, PTGR1 and PTPN14) have been revealed. These genes were able to predict illudin susceptibility in blind trials with an accuracy of up to 100%. The gene expression, DNA mutation, DNA methylation, and protein expression status of these 10 genes were further computer-calculated for their correlation with ildin (LP-184) susceptibility. As shown in Table 1, it was revealed that 3 out of 10 genes were significantly highly correlated with the biological activity of ildin at the multiomics level. These genes are PTGR1, PTPN14, and ASPH. These three genes also had the highest gene weighting in terms of relative importance in determining illudin (LP-184) susceptibility in FIG. These three genes were found to be the most prominent genes in classifying samples as illudin responders or non-responders, as shown in FIG. Taken together, a novel set of genes was established to determine susceptibility to ildin (LP-184) and predict response in cancer.

Example 1

Claims (19)

A method of treating solid tumor cancer using targeted drug treatment.
The following formula:

Including identifying patients with cancer who are sensitive to treatment with the compounds of
In the formula, R1, R2 and R3 are independently (C1-C4) alkyl, methyl or hydroxyl, the method. The method of claim 1, further comprising measuring the expression level of PTGR1 of the combination in a biological sample. The method of claim 1, further comprising measuring the expression level of PTPN14 in a biological sample. The method of claim 1, further comprising measuring the expression level of ASPH in a biological sample. The method of claim 1, wherein the cancer is newly diagnosed, relapsed, or refractory. The method of claim 1, further comprising modifying the targeted drug therapy based on gene expression. The method of claim 2, wherein PTGR1, PTPN14, or ASPH is methylated. Illudin has the following structure:

The method according to claim 1. The method according to 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. A method of treating a solid tumor or a method of managing a solid tumor treatment,
The following formula:

To identify a patient with solid tumor cancer who is sensitive to treatment with illdin, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and to the patient, the therapeutic efficacy of the ildin. Methods including, in which a dose is administered. 10. The method of claim 10, wherein the biological sample is a blood, plasma, serum or tissue biopsy. 11. The method of claim 11, further comprising measuring the expression level of PTGR1 in the biological sample. 12. The method of claim 12, further comprising measuring the expression level of PTPN14 in the biological sample. 12. The method of claim 12, further comprising measuring the expression level of ASPH in the biological sample. A method of predicting treatment responsiveness in patients with solid tumors.
Obtaining a biological sample from the patient,
Measuring the expression levels of PTGR1, PTPN14, ASPH, or a combination thereof in the biological sample, and the expression levels in the biological sample and the biological sample from the subject without solid cancer. Including, comparing with the expression level of
The increase in expression levels in the biological sample from the patient as compared to the level of the subject without the solid tumor is as follows:

A method of demonstrating the potential for an effective response to treatment with a compound of, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. A kit for determining whether illudins may have anticancer effects in cancer, comparing the levels of PTGR1, PTPN14, ASPH, or a combination thereof in cancer with those from a subject with a solid tumor. A kit comprising means for determining by comparison with the normal value of the biological sample from the patient. The kit according to 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. A kit for determining whether ildins may have anticancer effects in cancer, such as mRNA, DNA and / or protein levels corresponding to PTGR1, PTPN14, ASPH, or combinations thereof in cancer cells. A kit containing means for determining. The illudin is as follows:

The kit according to claim 16 or 18.

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