EP3863615A1 - Procédés de traitement de cancers à tumeur solide à l'aide d'illudines et de biomarqueurs - Google Patents

Procédés de traitement de cancers à tumeur solide à l'aide d'illudines et de biomarqueurs

Info

Publication number
EP3863615A1
EP3863615A1 EP19872565.7A EP19872565A EP3863615A1 EP 3863615 A1 EP3863615 A1 EP 3863615A1 EP 19872565 A EP19872565 A EP 19872565A EP 3863615 A1 EP3863615 A1 EP 3863615A1
Authority
EP
European Patent Office
Prior art keywords
cancer
biological sample
expression
illudin
level
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP19872565.7A
Other languages
German (de)
English (en)
Other versions
EP3863615A4 (fr
Inventor
Aditya KULKAMI
Yuvanesh VEDARAJU
Umesh KATHAD
Arun ASAITHAMBI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lantern Pharma Inc
Original Assignee
Lantern Pharma Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lantern Pharma Inc filed Critical Lantern Pharma Inc
Publication of EP3863615A1 publication Critical patent/EP3863615A1/fr
Publication of EP3863615A4 publication Critical patent/EP3863615A4/fr
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • This invention relates to a marker or markers for use in determination of the sensitivity of a cancer patient to an anti-cancer agents (e.g., illudins) to be administered thereto, which marker can determine whether or not the cancer of the patient has a therapeutic response to the anti cancer agent, and to application of the marker.
  • an anti-cancer agents e.g., illudins
  • Illudins have been chemically modified and used to treat cancer.
  • Irofulven an illudin, is a chemically modified version of the fungal toxin Illudin S. It is a DNA-alkylating agent that has an unusual mechanism.
  • This illudin is a DNA and protein-damaging agent that targets rapidly dividing cells of malignant tumors. It enters the tumor cells where it interferes with DNA replication and cell division by binding to DNA and to protein targets. This leads the tumor cells to shut down and consequently die (apoptosis).
  • a study determined that at certain doses tumor cells were highly susceptible to Irofulven’ s dual damaging activity while normal cells showed only marginal response to the cell-killing drug.
  • This application relates to methods for determining the likelihood that a subject suffering from a solid tumor cancer will benefit from treatment with an illudin. Further, there are also methods for treatment based on such determination.
  • markers prostaglandin reductase 1 (PTGR1), Protein Tyrosine Phosphatase Non-Receptor Type 14 (PTPN14), Aspartate Beta-Hydroxylase (ASPH) together with one or more genes or alone are used in methds.
  • the protein or gene may be expressed or methylated.
  • a method of treating solid tumor cancer with a targeted drug therapy comprising: [0008] identifying a patient having cancer sensitive to treatment with a compound of the formula:
  • Rl, R2 and R3 are independently (C1-C4) alkyl, methyl, or hydroxyl.
  • 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.
  • primate e.g., human
  • cow, pig, sheep, goat horse
  • dog cat
  • rabbit rat
  • patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject, in one embodiment, a human.
  • treat means to include alleviating or abrogating a condition, or one or more of the symptoms associated with the condition; or alleviating or eradicating the cause(s) of the condition itself.
  • the terms "manage,” “managing,” and “management” encompass preventing the recurrence of the specified disease, disorder, or condition in a patient who has already suffered from the disease, disorder, or condition, and/or lengthening the time that a patient who has suffered from the disease, disorder, or condition remains in remission.
  • the terms encompass modulating the threshold, development and/or duration of the disease, disorder, or condition, or changing the way that a patient responds to the disease, disorder, or condition.
  • prevent are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition.
  • sensitivity and “sensitive” when made in reference to treatment with compound is a relative term which refers to the degree of effectiveness of the compound in lessening or decreasing the progress of the disease, disorder, or condition being treated.
  • increased sensitivity or “sensitive to treatment” when used in reference to treatment of a disease, disorder, or condition in connection with a compound refers to an increase of at least 3%, in particular at least 5%, or more, in the effectiveness of the treatment.
  • 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 the disease, disorder, or condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of the disease, disorder, or condition.
  • the term "therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the disease, disorder, or condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • an "effective patient response” refers to any increase in the therapeutic benefit to the patient.
  • An “effective patient response” can be, for example, a 5%, 7.5%, 10%,
  • 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% decrease in the physical symptoms of a disease, disorder, or condition.
  • an "effective patient response” can also be, for example, a 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 increase in the response of the patient, as measured by any suitable means, such as gene expression, cell counts, assay results, etc.
  • An improvement in the disease, disorder, or condition can be characterized as a complete or partial response.
  • “Complete response” refers to an absence of clinically detectable disease with normalization of any previously abnormal radiographic studies, bone marrow, and cerebrospinal fluid (CSF) or abnormal monoclonal protein measurements.
  • Partial response refers to at least about a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% decrease in all measurable disease, disorder, or condition burden (i.e., the number of malignant cells present in the subject, or the measured bulk of tumor masses or the quantity of abnormal monoclonal protein) in the absence of new lesions.
  • treatment contemplates both a complete and a partial response.
  • refractory or resistant refers to a circumstance where patients, even after intensive treatment, do not respond to treatment.
  • patients may have residual cancer cells (e.g., leukemia or lymphoma cells) in their lymphatic system, blood and/or blood forming tissues (e.g., marrow).
  • residual cancer cells e.g., leukemia or lymphoma cells
  • blood and/or blood forming tissues e.g., marrow
  • determining generally refer to any form of measurement, and include determining if an element is present or not. These terms include both quantitative and/or qualitative determinations.
  • Assessing 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 or absent.
  • isolated and purified refer to isolation of a substance (such as DNA/mRNA or protein) such that the substance comprises a substantial portion of the sample in which it resides, i.e. greater than the substance is typically found in its natural or un-isolated state.
  • a substantial portion of the sample comprises, e.g., 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, usually up to about 90%-l00% of the sample.
  • a sample of isolated DNA/mRNA can 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 according to density.
  • sample as used herein relates to a material or mixture of materials, typically, although not necessarily, in fluid form, containing one or more components of interest.
  • Biological sample refers to a sample obtained from a biological subject, including sample of biological tissue or fluid origin, obtained, reached, or collected in vivo or in situ.
  • a biological sample also includes samples from a region of a biological subject containing precancerous or cancer cells or tissues. Such samples can be, but are not limited to, organs, tissues, fractions and cells isolated from a mammal.
  • Exemplary biological samples include but are not limited to cell lysate, a cell culture, a cell line, a tissue, oral tissue, gastrointestinal tissue, an organ, an organelle, a biological fluid, a blood sample, a urine sample, a skin sample, and the like.
  • Biological samples include but are not limited to whole blood, partially purified blood, PBMCs, tissue biopsies, and the like.
  • optically pure means a composition that comprises one optical isomer of a compound and is substantially free of other isomers of that compound.
  • 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.
  • a typical optically pure compound comprises greater than about 80% by weight of one enantiomer of the compound and less than about 20% by weight of other enantiomers 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 enantiomers 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 enantiomers 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 enantiomers 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 enantiomers of the compound.
  • the Ri, R 2 and R 3 are independently (C1-C4) alkyl, methyl, or hydroxyl.
  • the term illudin may include HydroxyMethyl Acylfulvene (HMAF, Irofulven), which has the following formula II:
  • illudin also may include (-)-HydroxyUreaMethylAcylfulvene, which has the following formula III
  • One member of the anti-cancer agent sensitivity determination marker includes gene markers prostaglandin reductase 1 (PTGR1), Protein Tyrosine Phosphatase Non-Receptor Type 14 (PTPN14), Aspartate Beta-Hydroxylase (ASPH) together with one or more genes or alone.
  • the protein gene may be expressed or methylated.
  • Prostaglandin reductase 1 (PTGR1) is a highly inducible enzyme with enone reductase activity.
  • the marker PTGRI was correlated with sensitivity to illudin-based treatments or correlated with true responders to illudin-based treatments.
  • the use of the marker can reduce the gaps in the treatment of cancers (e.g., prostate cancers) by developing predictive biomarker-based screening tests enabling precision medicine-based therapies to patients.
  • cancers e.g., prostate cancers
  • the inventors have discovered that detection of solid tumor-associated mutated nucleic acid or protein sequences circulating in subjects with a solid tumor cancer that can accurately determine whether the subject is sensitive to a treatment with an illudin.
  • the DNA of the PTGR1, PTPN14, ASPH genes are methylated.
  • DNA methylation is a process by which methyl groups are added to the DNA molecule.
  • Methylation can change the activity of a DNA segment without changing the sequence.
  • DNA methylation When located in a gene promoter, DNA methylation typically acts to repress gene transcription.
  • a method of treating or managing solid tumor cancer includes identifying a patient having cancer sensitive to treatment with an illudin of the formula:
  • illudin or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; and administering to the patient a therapeutically effective amount of the illudin.
  • a method of treating or managing solid tumor treatment includes identifying a patient having solid tumor cancer sensitive to treatment with an illudin having the formula:
  • a method for predicting response to treatment in a patient having a solid tumor comprising: obtaining a biological sample from the patient; measuring the level of expression of PTGR1, PTPN14, ASPH or a combination thereof in the biological sample; and comparing the level of expression in the biological sample to that of a biological sample from a subject not having a solid cancer; wherein an increased level of the expression in the biological sample from the patient relative to that from the subject not having the solid tumor indicates a likelihood of an effective response to the treatment with a compound of the formula:
  • a method for predicting response to treatment in a patient having a solid tumor comprising: obtaining a biological sample from the patient; measuring the level of expression of PTGR1, PTPN14, ASPH or a combination thereof in the biological sample; and comparing the level of the expression of PTGR1, PTPN14, ASPH or a combination thereof in the biological sample to that of a biological sample from a subject not having a solid tumor; wherein a decreased level of expression of PTGR1, PTPN14, ASPH or a combination thereof in the biological sample from the patient relative to that from the subject not having a solid tumor indicates a likelihood of an effective response to the treatment with a compound of the formula: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
  • a method of treating or managing solid tumor cancer comprising: identifying a patient having solid tumor cancer sensitive to treatment with an illudin, or a pharmaceutically acceptable salt; and administering to the patient a therapeutically effective amount of the compound.
  • methods provided herein further comprise administering a therapeutically effective amount of an additional active agent, which is illudin.
  • the illudin is administered once on day 1 of a 21 day cycle or another cycle.
  • the illudin may be administered with one or more second active ingredients.
  • active ingredients may be other anti-cancer agents or agents used to treat cancer patients.
  • the solid tumor cancer may be selected from the group consisting of colorectal cancer, pancreatic cancer, primary liver cancers, kidney cancer, ovarian cancer, uterine cancer, lung cancer, breast cancer, prostate cancer, sarcomas, and adipose tissue cancer.
  • one or more of the following genes may be used as a marker with PTGR1 to determine sensitivity to an illudin-based anticancer agent: TNFRSF1B, LCK, TAL1,
  • GNG12 S100A10, CD247, ATP1B1, LAMC1, PTPRC, PTPN7, PTPN14, CAPN2, ENAH, LCT, CXCR4, ITGA4, C ASP 10, HDAC4, NUP210, WWTR1, PFN2, MLF1, CD38, RHOH,
  • ITK ITK, LCP2, HIST1H3B, MYB, IKZF1, PIK3CG, MET, NRF1, TRBC1, PTPRN2, PTK2B, ASPH, NFIB, CNTRL, PRKCQ, MYOF, CTBP2, LM02, CD3D, TWF1, NCKAP1L, CKAP4, LCP1, CFL2, TJP1, ALDH1A2, TLE3, TNFRSF12A, PRKCB, NFATC3, WWOX, CBFA2T3, ATP2A3, GIPC1, HAUS5, MAP4K1, SDC4, APP, SLC38A5, WAS, and IL2RG .
  • one or more markers were combined with PTGR1 with one, more or all of the following genes with PTGR1 : PTPN14, ITGA4, HDAC4, ITK, D ZF1, PIK3CG, NRF1, ASPH, and PRKCQ.
  • the sensitivity can approach 100%.
  • the two markers PTGR1 and SDC4 may be used as the markers.
  • screening of an anti-cancer agent sensitivity enhancer can be performed through employment, as an index, of variation in expression of a PTGR1 combination of genes after exposure to the illudin-based anti -cancer agent. That is, a substance which decreases the PTGR1 combination of genes level before exposure to the illudin-based anti-cancer agent or which promotes variation in the expression or elevates the level after exposure to the illudin-based anti-cancer agent, in vitro or in vivo, enhances the sensitivity to the anti-cancer agent.
  • a substance which promotes variation in the expression or elevates the level after exposure to the anti-cancer agent corresponding to the target cancer cells can serve as a substance which enhances the sensitivity to the illudin-based anti-cancer agent (i.e., anti-cancer agent sensitivity enhancer).
  • a kit containing a protocol for measuring any of the substances present in the specimen is employed.
  • the kit contains a reagent for measuring any of these substances, an indication of an instruction manual for use of the reagent, standards for determining the presence or absence of sensitivity to the illudin-based anti-cancer agent, etc.
  • the standards include (relative) standard levels of these metabolism-related substances, a (relative) high threshold level, a (relative) low threshold level, factors affecting the measurements, the degree of the effects, etc. These substance levels may be set so as to suit the illudin-based anti-cancer agent selected. The sensitivity determination may be performed in the same manner on the basis of the standards.
  • Screening of an illudin-based anti-cancer agent can be performed by means of the illudin- based anti-cancer agent sensitivity determination marker as an index. That is, a substance which can vary the level of the anti-cancer agent sensitivity determination marker in vitro or in vivo is evaluated as an anti-cancer agent. For example, in an in vitro case, a substance which varies the anti-cancer agent sensitivity determination marker level in various cancer cells after exposure to the substance can serve as an anti-cancer agent. Also, when the anti-cancer agent sensitivity determination marker level in a cancer-bearing animal is varied after administration of a substance thereto, the substance can serve as an anti-cancer agent.
  • the anti-cancer agent is expected to exhibit a pharmacological effect, the increase in anti-cancer agent sensitivity determination marker level is observed before occurrence of tumor shrinkage or attaining cytocidal effect. Therefore, screening based on the anti-cancer agent sensitivity determination marker level as an index can realize, for a shorter period of time, determination whether or not the test substance serves as a useful anti-cancer agent, whereby efforts and cost involved in the development of anti-cancer agents are greatly expected to be reduced.
  • the cancer has no sensitivity to an anti-cancer agent, no pharmacological effect can be expected from the anti-cancer agent. If such a pharmaceutically impotent anti-cancer agent is continuously administered to the patient, the cancer may progress, and side effects may be aggravated.
  • the anti-cancer agent sensitivity determination marker may be employed not only to determine therapeutic response to the anti-cancer agent, but also to greatly contribute to prevention of aggravation of side effects, which would otherwise be caused by continuous administration of a pharmaceutically inactive anti-cancer agent.
  • the combination of the illudin-based anti-cancer agent sensitivity enhancer and the anti-cancer agent which is a sensitivity enhancement target of the enhancer may be a composition containing both ingredients, or a combined drug of preparations containing individual ingredients.
  • the reference value is obtained from the subject, as part of an on-going screening program.
  • the reference value may be obtained from a population of subjects who have no solid tumor cancer.
  • Cells for testing may be obtained by any method known in the art, including but not limited to as a surgical resection, as a biopsy for example but not limited to a needle biopsy, core biopsy, or aspirate, or collection from a fluid sample, such as blood, urine, cerebral spinal fluid, cystic fluid, etc.
  • Methods of 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.
  • Methods of measuring protein include but are not limited to mass spectrometry techniques, l-D or 2-D gel-based analysis systems, chromatography, enzyme linked immunosorbent assays (ELISAs), radioimmunoassays (RIA), enzyme immunoassays (EIA), Western Blotting, immunoprecipitation, and immunohistochemistry.
  • ELISAs enzyme linked immunosorbent assays
  • RIA radioimmunoassays
  • EIA enzyme immunoassays
  • Western Blotting immunoprecipitation
  • immunohistochemistry immunohistochemistry.
  • Antibody arrays or protein chips may also be employed.
  • That an anticancer effect is "likely" to be produced by an agent in a subject means that the subject, in the parameter or parameters being tested (e.g., level of PTGR1, PTPN14 and ASPH mRNA, methylated DNA and/or protein, expression of genes or exons listed in Example 1), is more similar to other subjects in which the agent produces a significant anticancer effect than to other subjects in which the agent does not produce a significant anticancer effect.
  • That an anticancer effect is "unlikely" to be produced by an agent in a subject means that the subject, in the parameter or parameters being tested, is more similar to other subjects in which the agent does not produce a significant anticancer effect than to other subjects in which the agent does produce a significant anticancer effect.
  • compositions can be used in the preparation of 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.
  • Pharmaceutical compositions and dosage forms provided herein can further comprise one or more excipients.
  • compositions and dosage forms provided herein can also comprise one or more second active ingredients. Consequently, pharmaceutical compositions and dosage forms provided herein comprise the active ingredients disclosed herein (e.g., an immunomodulatory compound). Examples of optional second, or additional, active ingredients are disclosed herein.
  • Kits and compositions for carrying out the methods provided herein are also provided.
  • kits useful 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 useful for determining the effect of an immunomodulatory compound.
  • the kit comprises a solid support, and a means for detecting the gene, protein, or glycoprotein expression of at least one biomarker in a biological sample. Such a kit may employ, for example, a dipstick, a membrane, a chip, a disk, a test strip, a filter, a microsphere, a slide, a multiwell plate, or an optical fiber.
  • the solid support of the kit can be, for example, a plastic, silicon, a metal, a resin, glass, a membrane, a particle, a precipitate, a gel, a polymer, a sheet, a sphere, a polysaccharide, a capillary, a film, a plate, or a slide.
  • the biological sample can be, for example, a cell culture, a cell line, a tissue, an oral tissue, gastrointestinal tissue, an organ, an organelle, a biological fluid, a blood sample, a urine sample, or a skin sample.
  • kits provided herein comprises an illudin compound provided herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof. Kits may further comprise additional active agents, including but not limited to those disclosed herein.
  • Example 1 analyses of in vitro Illudin (LP-184) sensitivity data from a panel of cancer cell lines with known multi-omic molecular profiles yielded a signature of 10 genes (ASPH, HDAC4, IKZF1, ITGA4, ITK, NRF1, PIK3CG, PRKCQ, PTGR1, and PTPN14) capable of predicting illudin sensitivity with up to or including 100% accuracy on blind testing.
  • the gene expression, DNA mutation, DNA methylation and protein expression status of these 10 genes was further computed as a correlation with Illudin (LP-184) sensitivity.
  • FIG. 1 shows the relative importance of an exemplary gene signature for
  • PTGR1 Prostaglandin Reductase 1
  • ASPH ASPH
  • FIG 2. shows PTGR1 and PTPN14 association with positive response to

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Abstract

La présente invention concerne des procédés de détermination de la probabilité qu'un sujet souffrant d'un cancer à tumeur solide pourrait bénéficier du traitement avec une illudine. En outre, l'invention concerne également des procédés de traitement en fonction d'une telle détermination. Dans plusieurs modes de réalisation, les marqueurs prostaglandine réductase (1) (PTGR1), protéine tyrosine phosphatase type non-récepteur 14 (PTPN14), l'aspartate bêta-hydroxylase (ASPH) conjointement à un ou plusieurs gènes ou seul peuvent être utilisés pour améliorer ou guider le traitement avec une illudine. Dans certains modes de réalisation, la protéine ou le gène peut être exprimé ou méthylé.
EP19872565.7A 2018-10-14 2019-10-14 Procédés de traitement de cancers à tumeur solide à l'aide d'illudines et de biomarqueurs Pending EP3863615A4 (fr)

Applications Claiming Priority (2)

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US201862745382P 2018-10-14 2018-10-14
PCT/US2019/056039 WO2020081414A1 (fr) 2018-10-14 2019-10-14 Procédés de traitement de cancers à tumeur solide à l'aide d'illudines et de biomarqueurs

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EP3863615A1 true EP3863615A1 (fr) 2021-08-18
EP3863615A4 EP3863615A4 (fr) 2022-08-03

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EP (1) EP3863615A4 (fr)
JP (2) JP2022513349A (fr)
CN (1) CN113194934B (fr)
AU (2) AU2019361781A1 (fr)
CA (1) CA3116552A1 (fr)
WO (1) WO2020081414A1 (fr)

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EP4146181A4 (fr) * 2020-05-08 2024-10-09 Lantern Pharma Inc. Méthode de traitement du cancer du pancréas
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JP2025111438A (ja) 2025-07-30
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