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JP-2026514202-A - Methods for predicting response to cancer treatment

JP2026514202AJP 2026514202 AJP2026514202 AJP 2026514202AJP-2026514202-A

Abstract

The present invention relates to a method for predicting the response of cancer patients to anti-cancer treatment based on the detection of biomarkers. The present invention also relates to a treatment method, a method for selecting cancer patients to be treated, or a method for selecting a treatment method suitable for cancer patients, based on the detection of the biomarkers.

Inventors

  • カサクベルタ セルラ、シルビア
  • ボーリュー、マリー－エーヴ
  • ソウセック、ラウラ

Assignees

  • ペプトミク エセ．エレ．
  • インスティテュシオ・カタラナ・デ・レセルカ・イ・エスチュディス・アヴァンカス
  • フンダシオ プリバダ インスティトゥト ディンベスティガシオ オンコロジカ デ バル エブロン

Dates

Publication Date
20260507
Application Date
20231024
Priority Date
20221025

Claims (15)

  1. An in vitro method for predicting the clinical response of a patient with cancer to an anti-cancer treatment selected from the following: a) A polypeptide containing the sequence of Sequence ID No. 1 or a functionally equivalent variant thereof; b) A polypeptide comprising the sequence of Sequence ID No. 1 or a functionally equivalent variant thereof, and a conjugate comprising a chemical moiety that promotes cellular uptake of the polypeptide or the functionally equivalent variant thereof; c) A polynucleotide encoding the polypeptide of a) or the conjugate of b); d) A vector comprising the polynucleotide described in c); and e) A cell selected from the group consisting of cells capable of secreting the polypeptide described in a) or the conjugate described in b) into a culture medium. The method in question is as follows: (i) determining the level of at least one biomarker selected from the group consisting of MIP-1β, CD62E, IL-8, GM-CSF, and IL-1α in a sample from the subject, and (ii) comparing the level of the at least one biomarker with a reference value, Here, A method wherein a decrease in the level of the at least one biomarker relative to the reference value indicates a good clinical response of the subject to the anti-cancer treatment, or equal to or an increase in the level of the at least one biomarker relative to the reference value indicates a poor clinical response of the subject to the anti-cancer treatment.
  2. The method according to claim 1, wherein the favorable clinical response is stabilization of the disease, and the unfavorable clinical response is progression of the disease.
  3. An in vitro method for selecting a customized treatment for a patient with cancer, (i) determining the level of at least one biomarker selected from the group consisting of MIP-1β, CD62E, IL-8, GM-CSF, and IL-1α in a sample from the subject, and (ii) comparing the level of the at least one biomarker with a reference value, Here, - A decrease in the level of at least one of the biomarkers relative to the reference value indicates that the selected treatment includes a drug selected from the group consisting of: a) A polypeptide containing the sequence of Sequence ID No. 1 or a functionally equivalent variant thereof; b) A polypeptide comprising the sequence of Sequence ID No. 1 or a functionally equivalent variant thereof, and a conjugate comprising a chemical moiety that promotes cellular uptake of the polypeptide or the functionally equivalent variant thereof; c) A polynucleotide encoding the polypeptide of a) or the conjugate of b); d) A vector comprising the polynucleotide described in c); and e) A cell capable of secreting the polypeptide described in a) or the conjugate described in b) into a culture medium: or, - Equivalent or increased levels of at least one of the biomarkers relative to the reference value indicate that the selected treatment does not include any drugs selected from the group consisting of: a) A polypeptide containing the sequence of Sequence ID No. 1 or a functionally equivalent variant thereof; b) A polypeptide comprising the sequence of Sequence ID No. 1 or a functionally equivalent variant thereof, and a conjugate comprising a chemical moiety that promotes cellular uptake of the polypeptide or the functionally equivalent variant thereof; c) A polynucleotide encoding the polypeptide of a) or the conjugate of b); d) A vector comprising the polynucleotide described in c); and e) A cell capable of secreting the polypeptide described in a) or the conjugate described in b) into a culture medium. The way of doing so.
  4. An in vitro method for selecting a subject with cancer for treatment including a drug selected from the following group, a) A polypeptide containing the sequence of Sequence ID No. 1 or a functionally equivalent variant thereof; b) A polypeptide comprising the sequence of Sequence ID No. 1 or a functionally equivalent variant thereof, and a conjugate comprising a chemical moiety that promotes cellular uptake of the polypeptide or the functionally equivalent variant thereof; c) A polynucleotide encoding the polypeptide of a) or the conjugate of b); d) A vector comprising the polynucleotide described in c); and e) A cell capable of secreting the polypeptide described in a) or the conjugate described in b) into a culture medium. The method includes the following: (i) determining the level of at least one biomarker selected from the group consisting of MIP-1β, CD62E, IL-8, GM-CSF, and IL-1α in a sample from the subject; and (ii) comparing the level of the at least one biomarker to a reference value, and if a decrease in the level of the at least one biomarker relative to the reference value is detected, the patient is selected for the treatment.
  5. The sample is blood, serum, or plasma. The method according to any one of claims 1 to 4.
  6. The method according to any one of claims 1 to 5, wherein the level of at least one biomarker determined is either at the mRNA level or the protein level.
  7. The method according to claim 6, wherein the level of at least one biomarker protein is determined by an immunoassay.
  8. The method according to any one of claims 1 to 7, wherein the anti-cancer treatment includes the use of a polypeptide comprising SEQ ID NO: 4.
  9. The method according to any one of claims 1 to 8, further comprising determining the level of at least one additional biomarker selected from the group consisting of MCP-1, ICAM-1, IFN-gamma, IL-1β, IL-12, and combinations thereof.
  10. Drugs selected from the following group: a) A polypeptide containing the sequence of Sequence ID No. 1 or a functionally equivalent variant thereof; b) A polypeptide comprising the sequence of Sequence ID No. 1 or a functionally equivalent variant thereof, and a conjugate comprising a chemical moiety that promotes cellular uptake of the polypeptide or the functionally equivalent variant thereof; c) A polynucleotide encoding the polypeptide of a) or the conjugate of b); d) A vector comprising the polynucleotide described in c); and e) A cell capable of secreting the polypeptide described in a) or the conjugate described in b) into a culture medium, A drug for use in the treatment of a target cancer, wherein the target is identified as a good responder to the drug by the method of claim 1 or 2 or any one of claims 6 to 10, or the treatment is selected by the method of claim 3 or any one of claims 5 to 9.
  11. A kit comprising a specific reagent for determining the expression level of at least one biomarker selected from the group consisting of MIP-1β, CD62E, IL-8, GM-CSF, and IL-1α.
  12. The kit according to claim 11, further comprising a reagent specific for determining the expression level of at least one additional biomarker selected from the group consisting of MCP-1, ICAM-1, IFN-γ, IL-1β, IL-12, and combinations thereof.
  13. The kit according to claim 11 or 12, wherein the reagent is an antibody capable of specifically recognizing at least one biomarker.
  14. A kit according to any one of claims 11 to 13, wherein a reagent specific for determining the expression level of at least one biomarker constitutes at least 10% of the total amount of reagents comprising the kit.
  15. The use of a reagent specific for determining the expression level of at least one biomarker selected from the group consisting of MIP-1β, CD62E, IL-8, GM-CSF, IL-1α, MCP-1, ICAM-1, IFN-γ, IL-1β, and IL-12, or the kit described in any one of claims 11 to 14, in the method according to any one of claims 1 to 9.

Description

Field of Invention This invention relates to the field of cancer, and more specifically, to a method for predicting the response of a patient diagnosed with cancer to anti-cancer treatment based on the detection of biomarkers in a sample of the patient. Furthermore, this invention relates to a method for selecting a customized treatment appropriate to the patient, or a method for selecting a patient to receive treatment with an anti-cancer agent, and to anti-cancer agents used in the treatments mentioned in the method based on the detection of biomarkers. Moreover, this invention relates to a kit and its use in the method. Background of the Invention Cancer is the leading cause of death worldwide, accounting for nearly 10 million deaths in 2020. It represents a large subset of diseases characterized by the uncontrolled growth of abnormal cells. Myc activity is strictly regulated in normal cells, with higher levels in proliferating cells and lower levels in non-proliferating cells. Abnormally elevated or dysregulated Myc activity is associated with most cancers, often appearing as highly malignant, poorly differentiated, angiogenic, and treatment-resistant tumors. Omomyc is a dominant-negative Myc mutant containing the b-HLH-LZ domain of Myc and possessing four amino acid substitutions in the Myc leucine zipper (Soueck, L. et al., 1998, Oncogene 17, 2463–2472; Soueck, L. et al. (2002), Cancer Res 62: 3507–3510). The amino acid substitutions E61T, E68I, R74Q, and R75N alter the protein's dimerization specificity, but its ability to bind to its natural partner Max, homodimerize with itself, and heterodimerize with wild-type c-Myc, N-Myc, and L-Myc is maintained. Due to these properties, Omomyc can inhibit Myc-dependent gene transcriptional activation both in vitro and in vivo by inhibiting Myc's binding to the E-box, the DNA recognition binding site. Simultaneously, Omomyc potently enhances Myc-induced apoptosis in a Myc expression level-dependent manner, thereby strengthening Myc's transcriptional repressive activity. Thus, while Omomyc inhibits Myc's binding to the promoter E-box and the transcriptional activation of target genes, Miz-1-dependent promoter binding and transcriptional repression are maintained. In the presence of Omomyc, the Myc interactome is induced to repression, and its activity shifts from pro-tumorogenic to tumor-suppressive. WO2014/180889A8 demonstrates that the omomicupeptide itself efficiently permeates the cell membrane and translocates to the nucleus, where it exerts its tumor-suppressing effect. WO2018/011433A1 demonstrates that a variant of omomiq in which only cysteine is substituted with another amino acid is even more effective than omomiq in cancer treatment. However, cancer therapy has limitations, such as undesirable side effects and the development of congenital or acquired resistance. Selecting patients who are more likely to respond to treatment can avoid unnecessary treatment side effects and treatment delays, thereby improving cancer patient survival rates. Patients with tumors that are likely to be less responsive to cancer therapy may be candidates for alternative therapies. Therefore, personalized approaches are needed to better treat the disease, and more useful biomarkers are needed to predict cancer patients' responses to anti-cancer treatment. In a first embodiment, the present invention relates to an in vitro method for predicting the clinical response of a subject with cancer to an anti-cancer treatment selected from the following: a) A polypeptide containing the sequence of Sequence ID No. 1 or a functionally equivalent variant thereof; b) A polypeptide comprising the sequence of Sequence ID No. 1 or a functionally equivalent variant thereof, and a conjugate comprising a chemical moiety that promotes cellular uptake of the polypeptide or the functionally equivalent variant thereof; c) A polynucleotide encoding the polypeptide of a) or the conjugate of b); d) A vector comprising the polynucleotide described in c); and e) A cell selected from the group consisting of cells capable of secreting the polypeptide described in a) or the conjugate described in b) into a culture medium. The method in question is as follows: (i) determining the level of at least one biomarker selected from the group consisting of MIP-1β, CD62E, IL-8, GM-CSF, and IL-1α in a sample from the subject, and (ii) comparing the level of the at least one biomarker with a reference value, Here, The present invention relates to a system in which a decrease in the level of the at least one biomarker relative to the reference value indicates a favorable clinical response to the anti-cancer treatment of the subject, or a system in which the level of the at least one biomarker relative to the reference value is equal to or increases in the level of the at least one biomarker relative to the reference value indicates a poor clinical response to the anti-cancer treatment of the subject. In a second aspec