WO2022061001A1

WO2022061001A1 - Methods for patent selection and treatment of cancer

Info

Publication number: WO2022061001A1
Application number: PCT/US2021/050696
Authority: WO
Inventors: David Nelson
Original assignee: Splash Pharmaceuticals, Inc.
Priority date: 2020-09-16
Filing date: 2021-09-16
Publication date: 2022-03-24
Also published as: WO2022061001A8

Abstract

Methods of treatment for cancer using SPL-108 polypeptide (also known as A6) or an alternative CD44-modulating peptide based on the status of one or more markers such as but not limited to the p53 status of the cancer, BRCA status, HRD status, PARP inhibitor exposure status (e.g., whether or not the patient has had prior exposure to PARP inhibitors), etc. For example, the methods herein may feature selecting patients with a PAR Pi naive status. The methods herein may feature selecting patients with a combination of either wild type p53 status or non-null p53 status and a PARPi naive status. The methods herein may feature selecting patients with a combination of either wild type p53 status or non-null p53 status and a particular BRCA status. The methods herein may feature selecting patients with a combination of PARPi naive status and a particular BRCA status.

Description

METHODS FOR PATIENT SELECTION AND TREATMENT OF CANCER

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims benefit of U.S. Provisional Application No. 63/079,404 filed September 16, 2020, the specification(s) of which is/are incorporated herein in their entirety by reference.

[0002] This application is a continuation-in-part and claims benefit of PCT Application No. PCT/US21/32043, filed May 12, 2021 , the specification(s) of which is/are incorporated herein in their entirety by reference.

BACKGROUND OF THE INVENTION Field of the Invention

[0003] The present invention relates to methods for treating patients having cancer, including methods for selecting appropriate patients for administration of particular cancer therapeutics, e.g., methods for eliminating patients who are predicted to be non-responders.

Background Art

[0004] Mortality due to cancer is generally the result of metastasis of the primary tumor. Recurrence at distant sites following first-line therapy continues to be a major challenge. As a result, drugs that inhibit the metastatic process are of great interest. Metastasis and recurrence have been linked to a subpopulation of highly invasive tumorigenic cells that are characterized by the expression of CD44. CD44 is a complex multifunctional receptor modulating a variety of cellular processes. The peptide A6 (SPL-108) has been shown to bind to CD44 and to modulate CD44-mediated activity, helping to inhibit migration, invasion, and metastasis of tumor cells. A6 (SPL-108) is a capped, eight L-amino acid peptide having the sequence Ac-KPSSPPEE-NH₂ (SEQ ID NO: 1). FIG. 1 shows SPL-108 can inhibit CD-44, STATS, and PD-L1 in ovarian cancer cell lines. FIG. 2A and FIG. 2B shows progression free survival (PFS) in ovarian cancer patients treated with SPL-108. Treatment was most effective in patients with both (1) a p53 status that was either wild type or non-null (e.g., non-null referring to a status wherein p53 is not wild type but is also not null, e.g., p53 is at least partially active), and (2) no prior exposure to PARP inhibitor treatment. Without wishing to limit the present invention to any theory or mechanism, it is believed that prior PARP inhibitor (PARPi) exposure may inhibit efficacy of SPL-108 treatment, e.g., prior PARPi exposure could result in higher activity of CD44, STATS, and PD-L1, causing such patients to be non-responders, or to have reduced responses to CD44-modulating polypeptides such as but not limited to SPL-108. FIG. 3 shows projected PFS and overall response rate (ORR) based on stratifying patients having Marker #1 only (e.g., p53 status of wild type or non-null), Marker #2 only (no prior PARPi exposure), and both Marker #1 and Marker #2, relative to standard of care (SOC) and no patient stratification. Thus, Marker #2 helps predict or distinguish responding patients or non-responding patients.

BRIEF SUMMARY OF THE INVENTION

[0005] The present invention features methods of using SPL-108 (A6) polypeptide, a variant thereof, or a CD44-modulating peptides alone or in combination with other agents that allow for effectively treating cancer (e.g., ovarian cancer, endometrial cancer, breast cancer, colorectal cancer), alleviating symptoms of cancer (e.g., ovarian cancer, endometrial cancer, breast cancer, colorectal cancer), etc. wherein the administration of SPL-108 is based on the status of particular markers, e.g., the patient’s p53 status (e.g., selecting for patients with wild type p53 status or non-null status) and/or at least one other marker. In certain embodiments, the marker comprises the status of the patient's exposure to a PARP inhibitor (PARPi) (e.g., the marker may select for patients that have not had prior PARPi exposure). In some embodiments, the marker is BRCA status. In certain embodiments, the marker is homologous recombination deficiency (HRD) status. Other examples of markers may include but are not limited to levels of soluble CD44, PD-L1 levels, line of therapy, etc. Embodiments of the present invention can be freely combined with each other if they are not mutually exclusive.

[0006] Without wishing to limit the present invention to any theory or mechanism, it is believed that present invention advantageously provides a means for selecting patients that are the least likely to be non-responders or have reduced responses to CD44-modulating peptides for treatment with CD44-modulating peptides. Thus, the present invention better helps to avoid treating patients predicted to be non-responders or have reduced responses to CD44-modulating peptides, providing such patients with an opportunity to select an alternative treatment.

[0007] The present invention features a method of treating a cancer or a tumor, or inhibiting progression or metastasis of a cancer or a tumor in a patient in need thereof. In certain embodiments, the method comprises obtaining p53 status in a biological sample obtained from the patient, p53 status being selected from: wild type, non-null, and null; obtaining status of at least one additional marker; and administering one or a combination of therapeutic compositions or therapeutic interventions to the patient if the patient has either p53 wild type or p53 non-null status combined with a particular status of the at least one additional marker. The one or the combination of therapeutic compositions or therapeutic interventions treats the cancer or tumor, inhibits progression of the cancer or tumor, or inhibits metastasis of the cancer or tumor. The present invention also features a method of creating a patient cohort of one or more patients from a group of patients having a cancer. In certain embodiments, the method comprises obtaining p53 status in a biological sample obtained from each patient, p53 status being selected from: wild type, non-null, and null and/or obtaining status of at least one other/additional marker; and selecting patients from the group who have either p53 wild type or p53 non-null status combined with a particular status of the at least one additional marker to create a patient cohort. The cohort may be for administering one or a combination of therapeutic compositions or therapeutic interventions for treating or ameliorating said cancer. In certain embodiments, the method further comprises administering the one or the combination of therapeutic compositions or therapeutic interventions for treating or ameliorating said cancer.

[0008] In certain embodiments, the at least one additional marker is PARPi exposure status, wherein PARPi exposure status is selected from PARPi exposed or PARPi naive. In certain embodiments, the at least one additional marker is BRCA status, wherein BRCA status is selected from one or a combination of: BRCA1 positive and BRCA1 negative, BRCA1 ambiguous, BRCA2 positive, BRCA2 negative, and BRCA2 ambiguous. In certain embodiments, the at least one additional marker is HRD status, wherein HRD status is selected from HRD positive, HRD negative, and HRD unknown. In certain embodiments, the at least one additional marker is soluble CD44 level status. In certain embodiments, the at least one additional marker is PD-L1 level status. In certain embodiments, the at least one additional marker is line of therapy of the patient, e.g., 1^st line, 2^nd line, 3^rd, line, and 4^th line. In certain embodiments, the at least one additional marker is selected from: PARPi exposure status, BRCA status, HRD status, soluble CD44 level status, PD-L1 level status, and line of therapy. In certain embodiments, the at least one additional marker is Marker #2. In certain embodiments, the at least one additional marker is Marker #2 and Marker #3. In certain embodiments, the at least one additional marker is Marker #2, Marker #3, and Marker #4. In certain embodiments, the at least one additional marker is Marker #2, Marker #3, Marker #4, and Marker #5. In certain embodiments, the at least one additional marker is Marker #2, Marker #3, Marker #4, Marker #5, and Marker #6.

[0009] In certain embodiments, the one or a combination of therapeutic compositions or therapeutic interventions comprises SPL-108. In certain embodiments, the one or a combination of therapeutic compositions or therapeutic interventions comprises a variant of SPL-108. In certain embodiments, the one or a combination of therapeutic compositions or therapeutic interventions comprises a CD44-modulating polypeptide. In certain embodiments, the CD44-modulating polypeptide is a polypeptide comprising SEQ ID NO:1 or SEQ ID NO:2. In certain embodiments, the CD44-modulating polypeptide comprises a variant sequence of SEQ ID NO:1 , wherein the variant sequence comprises one or more amino acid mutation with respect to SEQ ID NO: 1 selected from: K1 to A; P2, P5, P6, or a combination thereof to A; S3, S4, or S3 and S4 to A; or E7, E8, or E7 and E8 to A, wherein the mutation retains CD44-modulating activity about equal to or greater than a polypeptide of SEQ ID NO:1. In certain embodiments, the one or a combination of therapeutic compositions or therapeutic interventions comprises a STATS inhibitor. STAT3 inhibitors may be selected from: HO-38678, H 0-4200, H-4318, LC28, STATS ODN, Stattic, siRNA-PLGA/CSO, M4 oncolytic virus, AG490, momelotinib, ruxolitinib, AZD1480, WP1066, DS-1029, MSL-2384, erlotinib, cetuximab, gefitinib, lapatinib, dasatinib, saratinib, tocilizumab, siltuximab, or a combination thereof. In certain embodiments, the one or a combination of therapeutic compositions or therapeutic interventions comprises a PD-L1 inhibitor.

[0010] In certain embodiments, the biological sample is selected from a group consisting of tissue, blood, and cells, saliva, and/or cerebrospinal fluid (CSF). In certain embodiments, the tissue further comprises fresh tissue, frozen tissue, and/or formalin-fixed, paraffin-embedded (FFPE).

[0011] In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is colorectal cancer. In certain embodiments, the cancer is a solid tumor or hematological cancer. In certain embodiments, the cancer is an ovarian cancer or the tumor is an ovarian cancer-associated tumor. In certain embodiments, the cancer is selected from a group consisting of ovarian cancer, breast cancer, colorectal cancer, prostate cancer, head and neck cancer, endometrial cancer, primary peritoneal cancer, liver cancer, glioblastoma, or a combination thereof. In certain embodiments, the cancer is resistant or refractory to treatment with chemo-, immuno-, gene, and/or radiation therapy.

[0012] In certain embodiments, the one or the combination of therapeutic compositions or therapeutic interventions is administered QD or BID. In certain embodiments, the one or the combination of therapeutic compositions or therapeutic interventions is administered during the first period continuously and without a rest period. In certain embodiments, the administration of the one or the combination of therapeutic compositions or therapeutic interventions is parenteral administration. In certain embodiments, the one or the combination of therapeutic compositions or therapeutic interventions is administered by transdermal administration.

[0013] In certain embodiments, the method further comprises administering a standard-of-care therapy, an anti-cancer agent, and/or radiation therapy. Sstandard-of-care therapy may comprise analgesics, anti-inflammatory agents, anti-proliferative agents, corticosteroids, hormone therapy, immunotherapy, gene therapy, radiotherapy, and/or biological response modifiers administered to the subject suffering from cancer. The anti-cancer agent may be selected from the group consisting of avastin, paclitaxel, paclitaxel analogues, docetaxel, cabazitaxel, doxorubicin, a checkpoint inhibitor, methotrexate, cisplatin, oxaliplatin, and carboplatin. In certain embodiments, the radiation therapy is selected from the group consisting of: X-Rays, gamma-Rays, UV-Rays, a particle beam, and decay of a radioactive isotope. Determining p53 status may comprise using standard laboratory techniques comprising polymerase chain reaction (PCR), real-time PCR, transcription mediated amplification (TMA) and reverse transcription PCR (RT-PCR), sequencing, microarray sequencing, next generation sequencing, IHC, or a combination thereof.

[0014] The present invention also features a method of creating a patient cohort of one or more patients from a group of patients having a cancer. In certain embodiments, the method comprises obtaining p53 status in a biological sample obtained from each patient, p53 status being selected from: wild type, non-null, and null; obtaining status of at least one additional marker; and eliminating patients from the group who have p53 null status and PARPi exposed status, wherein remaining patients in the group form a patient cohort for administering one or a combination of therapeutic compositions or therapeutic interventions for treating or ameliorating said cancer.

[0015] The present invention also features a method of treating an ovarian cancer or tumor, or inhibiting progression or metastasis of an ovarian cancer or a tumor in a patient in need thereof, said method comprising: obtaining p53 status in a biological sample obtained from the patient, p53 status being selected from: wild type, non-null, and null; obtaining status of at least one additional marker; and administering one or a combination of therapeutic compositions or therapeutic interventions to the patient if the patient has either p53 wild type or p53 non-null status combined with a particular status of the at least one additional marker, wherein the one or the combination of therapeutic compositions or therapeutic interventions treats the ovarian cancer or tumor, inhibits progression of the ovarian cancer or tumor, or inhibits metastasis of the ovarian cancer or tumor.

[0016] The present invention also features a method of treating an ovarian cancer or tumor, or inhibiting progression or metastasis of an ovarian cancer or a tumor in a patient in need thereof, said method comprising: obtaining p53 status in a biological sample obtained from the patient, p53 status being selected from: wild type, non-null, and null; obtaining status of PARPi exposure, wherein PARPi exposure status is selected from PARPi exposed or PARPi naive; and administering one or a combination of therapeutic compositions or therapeutic interventions to the patient if the patient has either p53 wild type or p53 non-null status combined with a PARPi naive status, wherein the one or the combination of therapeutic compositions or therapeutic interventions treats the ovarian cancer or tumor, inhibits progression of the ovarian cancer or tumor, or inhibits metastasis of the ovarian cancer or tumor.

[0017] The present invention also features a method of treating an ovarian cancer or tumor, or inhibiting progression or metastasis of an ovarian cancer or a tumor in a patient in need thereof, said method comprising: obtaining p53 status in a biological sample obtained from the patient, p53 status being selected from: wild type, non-null, and null; obtaining status of PARPi exposure, wherein PARPi exposure status is selected from PARPi exposed or PARPi naive; and administering SPL-8 to the patient if the patient has either p53 wild type or p53 non-null status combined with a PARPi naive status, wherein SPL-8 treats the ovarian cancer or tumor, inhibits progression of the ovarian cancer or tumor, or inhibits metastasis of the ovarian cancer or tumor.

[0018] The present invention also features a method of creating a patient cohort of one or more patients from a group of patients having an ovarian cancer, said method comprising: obtaining p53 status in a biological sample obtained from each patient, p53 status being selected from: wild type, non-null, and null; obtaining status of at least one additional marker (e.g., PARPi exposure status, BRCA status, HRD status, soluble CD44 level status, PD-L1 level status, line of therapy status); and selecting patients from the group who have either p53 wild type or p53 non-null status combined with a particular status of the at least one additional marker to create a patient cohort, the cohort is for administering one or a combination of therapeutic compositions or therapeutic interventions for treating or ameliorating said ovarian cancer.

[0019] In some embodiments, the method further comprises administering the one or the combination of therapeutic compositions or therapeutic interventions for treating or ameliorating said cancer. In some embodiments, the one or a combination of therapeutic compositions or therapeutic interventions comprises SPL-108, a variant of SPL-108, a CD44-modulating polypeptide, a STATS inhibitor, a PD-L1 inhibitor, or a combination thereof. In some embodiments, the ovarian cancer is resistant or refractory to treatment with chemo-, immuno-, gene, and/or radiation therapy.

[0020] The present invention also features a method of creating a patient cohort of one or more patients from a group of patients having an ovarian cancer, said method comprising: obtaining p53 status in a biological sample obtained from each patient, p53 status being selected from: wild type, non-null, and null; obtaining status of at least one additional marker; and eliminating patients from the group who have p53 null status and a particular status of the at least one additional marker, wherein remaining patients in the group form a patient cohort for administering one or a combination of therapeutic compositions or therapeutic interventions for treating or ameliorating said ovarian cancer.

[0021] In some embodiments, the at least one additional marker comprises one or a combination of: PARPi exposure status, BRCA status, HRD status, soluble CD44 level status, PD-L1 level status, and line of therapy. The present invention also features a method of creating a patient cohort of one or more patients from a group of patients having an ovarian cancer, said method comprising: obtaining status of at least one marker; and eliminating patients from the group who have a particular status of the at least one additional marker, wherein remaining patients in the group form a patient cohort for administering one or a combination of therapeutic compositions or therapeutic interventions for treating or ameliorating said ovarian cancer. In some embodiments, the at least one marker comprises one or a combination of: PARPi exposure status, p53 status, BRCA status, HRD status, soluble CD44 level status, PD-L1 level status, and line of therapy.

[0022] The present invention also features a method of treating an ovarian cancer or a tumor, or inhibiting progression or metastasis of an ovarian cancer or a tumor in a patient in need thereof, said method comprising: obtaining status of PARPi exposure, wherein PARPi exposure status is selected from PARPi exposed or PARPi naive; and administering one or a combination of therapeutic compositions or therapeutic interventions to the patient if the patient has a PARPi naive status, wherein the one or the combination of therapeutic compositions or therapeutic interventions treats the cancer or tumor, inhibits progression of the cancer or tumor, or inhibits metastasis of the ovarian cancer or tumor.

[0023] The present invention also features a method of creating a patient cohort of one or more patients from a group of patients having an ovarian cancer, said method comprising: obtaining status of PARPi exposure, wherein PARPi exposure status is selected from PARPi exposed or PARPi naive; and selecting patients from the group who have a PARPi naive status to create a patient cohort, the cohort is for administering one or a combination of therapeutic compositions or therapeutic interventions for treating or ameliorating said ovarian cancer. In some embodiments, the method further comprises obtaining status of an additional marker. In some embodiments, the additional marker is one or a combination of: p53 status, BRCA status, HRD status, soluble CD44 level status, PD-L1 level status, and line of therapy.

[0024] Any feature or combination of features described herein are included within the scope of the present invention provided that the features included in any such combination are not mutually inconsistent as will be apparent from the context, this specification, and the knowledge of one of ordinary skill in the art. Additional advantages and aspects of the present invention are apparent in the following detailed description and claims.

TERMS

[0025] A “CD44-modulating polypeptide” refers to a polypeptide that binds to CD44 and modulates its activity (e.g., signaling activity). A CD44-modulating polypeptide may be a polypeptide sequence described herein or, in some embodiments, an antibody that specifically binds to CD44 and inhibits its downstream signaling activity. In one embodiment, a CD44-modulating polypeptide may be a polypeptide sequence described herein or, in some embodiments, an antibody that disrupts or inhibits signaling activity of a CD44 dependent co-receptor. In certain instances the CD44 dependent co-receptor is a receptor tyrosine kinase (RTK) such as, for example, Met, Ran, or VEGFR. In still another embodiment a CD44-modulating polypeptide may be a polypeptide sequence described herein or, in some embodiments, an antibody that disrupts CD44 co-receptor function or association of a CD44 co-receptor with CD44 or another signaling protein. In one embodiment, a CD44-modulating polypeptide described herein binds to CD44 and inhibits CD44 signaling activity or association with one or more ABC transporters. The ABC transporter may be a multidrug resistant protein (e.g., MDR1). In certain embodiments, CD44 levels may be elevated upon radiation therapy. Exemplary CD-44 modulating polypeptides include polypeptides having homology to the CD44-v6 region of human CD44. Such peptides may include substitution variants, addition variants, or chemical derivatives thereof including peptidomimetics. In one embodiment, the CD44-modulating polypeptide described herein is a polypeptide having the amino acid sequence of AC-KPSSPPEE-NH₂ (SEQ ID NO:1 ), AC-NASAPPEE-NH₂ (SEQ ID NO:2), QETWFQNGWQGKNP (SEQ ID NOS), KEKWFENEWQGKNP (SEQ ID NO:4), or KEQWFGNRWHEGYR (SEQ ID NOS). Another CD44-modulating polypeptide may be QIRQQPRDPPTETLELEVSPDPAS (SEQ ID NOS). Such exemplary peptides may include substitution variants, addition variants, or chemical derivatives thereof including peptidomimetics. Other exemplary CD44-modulating peptides include those set forth in U.S. Patent Nos. 5,994,309; 6,696,416; and 6,963,587, 8,313,914, 8,697,629, and U.S. Patent Application Publication No. US2009192085.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

[0026] The features and advantages of the present invention will become apparent from a consideration of the following detailed description presented in connection with the accompanying drawings in which:

[0027] FIG. 1 shows SPL-108 can inhibit CD-44, STATS, and PD-L1 in ovarian cancer cell lines. [0028] FIG. 2A and FIG. 2B shows SPL-108 efficacy (PFS) based on a patient’s p53 status or prior PARPi therapy exposure.

[0029] FIG. 3 shows projected patient PFS (progression free survival) and ORR (overall response rate) based on enrolling patients using marker #1 (p53 wild type or non-null status), marker #2 (no prior PARPi exposure, e.g., PARPi naive), or both markers #1 and #2. The second criteria helps distinguish responding patients from non-responding patients.

DETAILED DESCRIPTION OF THE INVENTION

[0030] The present invention features methods of using SPL-108 (A6) polypeptide, a variant thereof, or a CD44-modulating peptides alone or in combination with other agents that allow for effectively treating cancer, alleviating symptoms of cancer, etc., wherein the use of SPL-108 is based on the patient’s p53 status (e.g., selecting for patients with wild type p53 status or non-null status) and at least one additional marker. In certain embodiments, the additional marker is BRCA status. In some embodiments, the additional marker is HRD (homologous recombination deficiency) status. In certain embodiments, the additional marker is PARPi exposure status, e.g., the patient’s prior PARPi exposure, wherein patients that have not had prior PARPi exposure are selected. The present invention is not limited to additional markers being BRCA status, HRD status, and PARPi exposure status.

[0031] In certain embodiments, the methods feature selecting for patients with wild type p53 status or non-null status and at least two additional markers. In certain embodiments, the methods feature selecting for patients with wild type p53 status or non-null status and at least three additional markers. The methods herein comprise determining the patient’s p53 status by evaluating p53 in a biological sample (e.g., tissue, cells, blood, saliva, cerebrospinal fluid CSF) obtained from the patient. As used herein, p53 status is selected from wild type, non-null, and null. Non-null p53 status refers to p53 that is not wild type but is also not null, and p53 is at least partially active. In certain embodiments, determining p53 status comprises using standard laboratory techniques comprising polymerase chain reaction (PCR), real-time PCR, transcription mediated amplification (TMA) and reverse transcription PCR (RT-PCR), sequencing, microarray sequencing, next generation sequencing, IHC, an alternative technique, or a combination thereof.

[0032] The methods may comprise determining the patient’s PARPi exposure status by asking the patient if he/she has used PARPi treatments or reviewing his/her medical records. As used herein, PARPi exposure status is selected from PARPi exposed if the patient has been previously treated with PARP inhibitors and PARPi naive if the patient has not been previously treated with PARP inhibitors. Determination of the p53 status and PARPi exposure status may not necessarily be in any particular order. PARP inhibitors include but are not limited to talazoparib, olaparib, or rucaparib.

[0033] In certain embodiments, patients having a wild type p53 status or non-null p53 status combined with a PARPi naive status are selected to be eligible to receive a treatment comprising a CD44-modulating polypeptide, for example: Ac-KPSSPPEE-NH₂ (SEQ ID NO:1) or an active variant thereof, or an alternative CD44-modulating peptide.

[0034] The methods may comprise determining the patient’s BRCA status. In certain embodiments, BRCA status may be selected from: BRCA1 positive, BRCA1 negative, BRCA1 ambiguous (e.g., a genetic variant of unknown significance), BRCA2 positive, BRCA2 negative, BRCA2 ambiguous (e.g., a genetic variant of unknown significance), etc. However, the present invention is not limited to these particular designations. In certain embodiments, patients having a wild type p53 status or non-null p53 status combined with a particular BRCA status are selected to be eligible to receive a treatment comprising a CD44-modulating polypeptide, for example: Ac-KPSSPPEE-NH₂ (SEQ ID NO:1) or an active variant thereof, or an alternative CD44-modulating peptide. The methods may comprise determining the patient’s HRD status. In certain embodiments, HRD status may be selected from: HRD positive, HRD negative, HRD unknown, etc. However, the present invention is not limited to these particular designations. In certain embodiments, patients having a wild type p53 status or non-null p53 status combined with a particular HRD status are selected to be eligible to receive a treatment comprising a CD44-modulating polypeptide, for example: Ac-KPSSPPEE-NH₂ (SEQ ID NO:1) or an active variant thereof, or an alternative CD44-modulating peptide. The methods may comprise determining the patient’s level of soluble CD44. In certain embodiments, patients having a wild type p53 status or non-null p53 status combined with a particular soluble CD44 level are selected to be eligible to receive a treatment comprising a CD44-modulating polypeptide, for example: Ac-KPSSPPEE-NH₂ (SEQ ID NO:1) or an active variant thereof, or an alternative CD44-modulating peptide. The methods may comprise determining the patient’s level of PD-L1. In certain embodiments, patients having a wild type p53 status or non-null p53 status combined with a particular PD-L1 level are selected to be eligible to receive a treatment comprising a CD44-modulating polypeptide, for example: Ac-KPSSPPEE-NH₂ (SEQ ID NO:1) or an active variant thereof, or an alternative CD44-modulating peptide.

[0035] During a first period, the treatment comprising a CD44-modulating polypeptide (e.g., SPL-108, an active variant thereof, SEQ ID NO: 1, an active variant thereof, or an alternative CD44-modulating peptide) may be administered to the screened or selected patient afflicted with a cancer/tumor in a manner sufficient to effectively treat the cancer/tumor.

[0036] Without wishing to limit the present invention to any particular theory or mechanism, the p53 status and the additional marker or additional markers (e.g., BRCA status, HRD status, PARPi exposure status, etc.) help predicts a positive response (e.g., complete response, partial response, stable disease, etc.) of the patient to treatment with a CD44-modulating polypeptide (e.g., SPL-108, an active variant thereof, or an alternative CD44-modulating peptide).

[0037] The present invention also features methods of using SPL-108 (A6) polypeptide, a variant thereof, or a CD44-modulating peptides alone or in combination with other agents that allow for effectively treating cancer alleviating symptoms of cancer, wherein the use of SPL-108 is based on the patient’s p53 status (e.g., selecting for patients with wild type p53 status or non-null status) and one or more additional markers as described above (e.g., Marker #2; Marker #2 and Marker #3; Marker #2 and Marker #4;Marker #3 and Marker #4; Marker #2, Marker #3, and Marker #4; etc.).

[0038] In certain embodiments, the additional marker is based on which line of therapy the patient is undergoing, e.g., first line therapy, a second line therapy, a third line therapy, or a fourth line therapy and beyond. In certain embodiments, the additional marker selects for patients in the 1^st, 2^nd, or 3^rd lines of therapy. In certain embodiments, the additional marker selects for patients in the 1^st line of therapy. In certain embodiments, the additional marker selects for the patients in the 1^st or 2^nd lines of therapy. The present invention is not limited to selection of patients in this manner. [0039] The present invention is not limited to additional markers disclosed herein, e.g., BRCA status, PARPi exposure status, HRD status, soluble CD44 levels, or PD-L1 levels. In certain embodiments, the additional marker is a biomarker other than BRCA status, PARPi exposure status, HRD status, soluble CD44 levels, or PD-L1 levels.

[0040] The present invention is not limited to the use of p53 status as a marker. For example, in certain embodiments, the method generally features obtaining status of at least one marker. In certain embodiments, the at least one marker may comprise PARPi exposure status. In certain embodiments, the at least one marker may comprise BRCA status. In certain embodiments, the at least one marker may comprise HRD status. In certain embodiments, the at least one marker may comprise soluble CD44 levels. In certain embodiments, the at least one marker may comprise PD-L1 levels. In certain embodiments, the at least one marker may comprise line of therapy. In certain embodiments, the at least one marker may comprise the at least one marker comprises p53 status, p53 status being selected from: wild type, non-null, and null. In certain embodiments, the at least one marker comprises one or a combination of: PARPi exposure status, p53 status, BRCA status, HRD status, soluble CD44 level status, PD-L1 level status, and line of therapy.

[0041] The method may further comprise administering one or a combination of therapeutic compositions or therapeutic interventions to the patient if the patient has a particular status of the at least one marker. The method may further comprise selecting patients from the group who have a particular status of the at least one marker to create a patient cohort.

[0042] Table 1 below describes non-limiting examples of markers and combinations of markers that may be used in methods of the present invention, e.g., for selecting patients for treatment, selecting patients for creating a patient cohort, etc.

TABLE 1

[0043] The present invention also descri >es methoc s of creating a patient cohort of one or more patients from a group of patients having a cancer. In certain embodiments, the method comprises obtaining status of at least one marker; and eliminating patients from the group who have a particular status of the at least one additional marker.

[0044] In some embodiments, the at least one marker is PARPi exposure status, wherein patients with a PARPi exposure status of PARPi exposed are eliminated from the group. In some embodiments, the at least one marker comprises p53 status and PARPi exposure status. In some embodiments, the at least one marker comprises BRCA status. In some embodiments, the at least one marker comprises HRD status. In some embodiments, the at least one marker comprises soluble CD44 level status. In some embodiments, the at least one marker comprises PD-L1 level status. In some embodiments, the at least one marker comprises line of therapy. In some embodiments, the at least one marker comprises one or a combination of: PARPi exposure status, p53 status, BRCA status, HRD status, soluble CD44 level status, PD-L1 level status, and line of therapy.

[0045] In certain embodiments, the method comprises obtaining p53 status in a biological sample obtained from each patient, p53 status being selected from: wild type, non-null, and null; obtaining status of at least one additional marker; and eliminating patients from the group who have p53 null status and a particular status of the at least one additional marker. In certain embodiments, the at least one additional marker is PARPi exposure status, wherein patients with a PARPi exposure status of PARPi exposed are eliminated from the group. In certain embodiments, the at least one additional marker comprises BRCA status. In certain embodiments, the at least one additional marker comprises HRD status. In certain embodiments, the at least one additional marker comprises soluble CD44 level status. In certain embodiments, the at least one additional marker comprises PD-L1 level status. The method of claim 40, wherein the at least one additional marker comprises line of therapy. In certain embodiments, the at least one additional marker comprises one or a combination of: PARPi exposure status, BRCA status, HRD status, soluble CD44 level status, PD-L1 level status, and line of therapy.

CD44-modulating polypeptides

[0046] In some embodiments, the CD44-modulating polypeptide comprises SEQ ID NO: 1 (SPL-108, A6) In some embodiments, the CD44-moduclating polypeptide comprises a variant sequence of SEQ ID NO:1. In certain embodiments, the variant of SEQ ID NO: 1 comprises one or more amino acid mutation with respect to SEQ ID NO:1 selected from: (a) K¹ to A; (b) P², P⁵, P⁶, or a combination thereof to A; (c) S³, S⁴, or S³ and S⁴ to A; or (d) E⁷, E⁸, or E⁷ and E⁸ to A. In certain embodiments, the mutation retains CD44 modulating activity substantially similar to or greater than the polypeptide of SEQ ID NO:1. In some embodiments, the mutation retains CD44 modulating activity of about equal to or greater than the polypeptide of SEQ ID NO:1.

[0047] The SEQ ID NO:1 may include a substitution of K to A; P to A; S to A; or E to A. In some embodiments, the sequence of SEQ ID NO:1 may be modified such that the CD44-modulating polypeptide includes a mutation of K¹ to A so long as the polypeptide retains activity about equal to or greater than the polypeptide of SEQ ID NO:1. In another embodiment, SEQ ID NO:1 may be modified to include mutation of P², P⁵, P⁶, or a combination thereof to A so long as the polypeptide retains activity about equal to or greater than the polypeptide of SEQ ID NO:1. In certain embodiments, P² may be mutated to A. In certain embodiments, P⁵ may be mutated to A. In certain embodiments, P⁶ may be mutated to A. In another embodiment, S³, S⁴, or S³ and S⁴ may be mutated to A so long as the polypeptide retains activity about equal to or greater than the polypeptide of SEQ ID NO:1. In another embodiment, E⁷, E⁸, or E⁷ and E⁸ may be mutated to A so long as the polypeptide retains activity about equal to or greater than the polypeptide of SEQ ID NO:1. It is to be understood that the above mutations may be combined in any manner to modify the polypeptide of SEQ ID NO:1 so long as the polypeptide retains activity about equal to or greater than the polypeptide of SEQ ID NO:1. SEQ ID NO:1 may include at least one glycosylation site. The glycosylation site may be an O-linked glycan on S³, S⁴, or S³ and S⁴ of SEQ ID NO:1. In other instances, the glycosylation site may be present in any one Ser or Thr residue of SEQ ID NOs:1-6.

[0048] In certain instances, the CD44-modulating polypeptide described herein may be a peptidomimetic as described herein of one or more amino acids sequences set forth herein. For example, a CD44-modulating polypeptide described herein may include N-terminal or C-terminal modifications such as acylation, esterification, carbamation, benzylation, or amidation. In particular embodiments, a CD44-modulating polypeptide includes an N-terminal modification. For example, the N-terminal of a CD44-modulating polypeptide described herein may be acylated or modified to a carbamate. In other instances the C-Terminal of a CD44-modulating polypeptide described herein may include modification. Such modification may include amidation. In another example, both the N-terminal and C-terminal of a CD44-modulating polypeptide described herein are modified. In such examples, the N-terminal may be acylated. In another example, a CD44-modulating polypeptide described herein may include incorporation of one or more D-amino acids. For example, incorporation of D-Lys, D-Ser, or D-Pro may be performed at positions 1 , 2, 3, 4, 5, or 6 of SEQ ID NO:1. In one embodiment each amino acid of SEQ ID NO:1 may be replaced with a D-amino acid. Incorporation of a D-amino acid into the sequence may decrease polypeptide degradation and/or enhance the half-life of a therapeutic composition including a CD44-modulating polypeptide described herein. It should be noted that modification of CD44-modulating peptides to include D-amino acids includes only those variants having activity comparable (e.g., about equal to or greater than) that of SEQ ID NO:1. In another example a CD44-modulating polypeptide includes an amide-bond isostere. An amide-bond isostere refers to an amide backbone replacement such as an carba (ψ[CΗ₂CΗ₂]), alkenes (ψ[CΗ=CΗ]), alkynes (ψ[C≡C]), methyleneoxy- (ψ[CΗ₂Ο]), methyleneamino- (ψ[CΗ₂ΝΗ]), urea (ψ[CΗ₂CΗ₂]), hydrazide (ψ[CONCH₂NCH₂]), ester (ψ[C(O)OCH₂], thioamide (ψ[CSΝΗ]), hydroxyamide (ψ[CΟΝ(CΗ)]) or phosphono (ψ[ΡΟ(CΗ)ΟΝΗ]).

Cancers and Tumors

[0049] Because patients with cancer have heterogeneous clinical manifestations and varying clinical outcomes, the treatment given to a patient may vary, depending, in part, on a combination of (1) prognosis, (2) responsiveness to therapy and (3) tolerance to therapy. The present disclosure allows for methods with varying treatment using the CD44-modulating polypeptides described herein.

[0050] The CD44-modulating polypeptides described herein may be useful for treating, preventing, and/or managing cancer or tumors of the skin tissues, organs, blood, and vessels, including, but not limited to, cancers of the bladder, bone, blood, brain, breast, cervix, chest, colon, endrometrium, esophagus, eye, head and neck, kidney, liver, lymph nodes, lung, mouth, ovaries, pancreas, peritoneal, prostate, rectum, stomach, testis, throat, pancreas, and uterus. In one embodiment, cancers include, but are not limited to, advanced malignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastase, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C & D colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi’s sarcoma, karotype acute myeloblastic leukemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma, follicular lymphoma, low grade follicular lymphoma, acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, malignant melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, primary peritoneal cancer, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unrescectable hepatocellular carcinoma, Waldenstrom’s macroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, or leiomyoma.

[0051] The cancer may be a solid tumor. The cancer may be a solid tumor selected from the group consisting of squamous cell carcinoma, nonsquamous cell carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer, renal cell carcinoma, ovarian cancer, breast cancer, prostate cancer, head and neck cancer, endometrial cancer, primary peritoneal cancers, glioblastoma, colorectal cancer, or pancreatic cancer, The cancer may be a hematological cancer. The hematological cancer may be leukemia, such as for example AML. The present invention is not limited to the aforementioned tissues associated with the cancer or tumor, nor the aforementioned types of cancers or tumors.

[0052] The methods herein may also include administering an additional therapeutic agent or therapeutic intervention, e.g., an anti-cancer agent. In certain embodiments, the anti-cancer agent comprises a taxane, a platinum agent, anthracyclin, a checkpoint inhibitor, or a combination thereof. In certain embodiments, the taxane is taxol, taxotere, paclitaxel, or cabazitaxel. In certain embodiments, the platinum agent is cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, or triplatin. In certain embodiments, the anti-cancer agent comprises a paclitaxel analogue, docetaxel, doxorubicin, or methotrexate. In certain embodiments, the anti-cancer agent comprises amrubicin, daunorubicin, epirubicin, idarubicin, doxorubicin, pirarubicin, or valrubicin. In certain embodiments, the anti-cancer agent is a PARP inhibitor (PARPi), e.g., if it is to be administered as a first exposure, e.g., the patient has no prior PARPi exposure. While exemplified above, the anti-cancer agent useful in the methods provided herein may include any known class of anti-cancer agents such as, for example, operations, alkylating agents, antimetabolites, anthracyclines, campothecins, vinca alkaloids, taxanes or platinums, as well as other antineoplastic agents known in the art. Such anti-cancer agent and antineoplastic agent classifications are known in the art and used in accordance with their plain and ordinary meaning. Such anti-cancer agents and anti-cancer agent classes may in certain instances provide anti-cancer activity in combination with each other. In one example, two or more different classes of anti-cancer agents described herein may be administered in combination and together with a CD44-modulating polypeptide described herein. In another example, one or more different classes of anti-cancer agents described herein may be administered in combination and together with a CD44-modulating polypeptide described herein and a radiation therapy as described herein.

[0053] In certain embodiments the methods described herein may include administering two or more anti-cancer agents in combination with a CD44-modulating polypeptide described herein.

[0054] Embodiments of the present invention may be freely combined with each other if they are not mutually exclusive. Although there has been shown and described the preferred embodiment of the present invention, it will be readily apparent to those skilled in the art that modifications may be made thereto which do not exceed the scope of the appended claims. Therefore, the scope of the invention is only to be limited by the following claims. In some embodiments, the figures presented in this patent application are drawn to scale, including the angles, ratios of dimensions, etc. In some embodiments, the figures are representative only and the claims are not limited by the dimensions of the figures. In some embodiments, descriptions of the inventions described herein using the phrase “comprising” includes embodiments that could be described as “consisting essentially of or “consisting of, and as such the written description requirement for claiming one or more embodiments of the present invention using the phrase “consisting essentially of” or “consisting of” is met.

Claims

WHAT IS CLAIMED IS:

1. A method of treating a cancer or a tumor, or inhibiting progression or metastasis of a cancer or a tumor in a patient in need thereof, said method comprising: (a) obtaining p53 status in a biological sample obtained from the patient, p53 status being selected from: wild type, non-null, and null; (b) obtaining status of at least one additional marker; and (c) administering one or a combination of therapeutic compositions or therapeutic interventions to the patient if the patient has either p53 wild type or p53 non-null status combined with a particular status of the at least one additional marker, wherein the one or the combination of therapeutic compositions or therapeutic interventions treats the cancer or tumor, inhibits progression of the cancer or tumor, or inhibits metastasis of the cancer or tumor.

2. A method of creating a patient cohort of one or more patients from a group of patients having a cancer, said method comprising: (a) obtaining p53 status in a biological sample obtained from each patient, p53 status being selected from: wild type, non-null, and null; (b) obtaining status of at least one additional marker; and (c) selecting patients from the group who have either p53 wild type or p53 non-null status combined with a particular status of the at least one additional marker to create a patient cohort, the cohort is for administering one or a combination of therapeutic compositions or therapeutic interventions for treating or ameliorating said cancer.

3. The method of claim 2 further comprising administering the one or the combination of therapeutic compositions or therapeutic interventions for treating or ameliorating said cancer.

4. The method of any of claims 1-3, wherein the at least one additional marker comprises: PARPi exposure status, BRCA status, HRD status, soluble CD44 level status, PD-L1 level status, line of therapy, or a combination thereof, wherein PARPi exposure status is selected from PARPi exposed or PARPi naive, wherein BRCA status is selected from one or a combination of: BRCA1 positive and BRCA1 negative, BRCA1 ambiguous, BRCA2 positive, BRCA2 negative, and BRCA2 ambiguous, wherein HRD status is selected from HRD positive, HRD negative, and HRD unknown.

5. The method of claim 4, wherein the line of therapy is selected from 1^st line, 2^nd line, 3^rd, line, and 4^th line.

6. The method of any of claims 1 -5, wherein the cancer is an ovarian cancer or the tumor is an ovarian cancer-associated tumor.

7. The method of any of claims 1 and 3-6, wherein the one or a combination of therapeutic compositions or therapeutic interventions comprises SPL-108.

8. The method of any of claims 1 and 3-6, wherein the one or a combination of therapeutic compositions or therapeutic interventions comprises SPL-108, a variant of SPL-108, a CD44-modulating polypeptide, a STAT3 inhibitor, a PD-L1 inhibitor, or a combination thereof.

9. The method of claim 8, wherein the STAT3 inhibitor is selected from HO-38678, HO-4200, H-4318, LC28, STATS ODN, Stattic, siRNA-PLGA/CSO, M4 oncolytic virus, AG490, momelotinib, ruxolitinib, AZD1480, WP1066, DS-1029, MSL-2384, erlotinib, cetuximab, gefitinib, lapatinib, dasatinib, saratinib, tocilizumab, siltuximab, or a combination thereof.

10. The method of any one of claims 1-9, wherein the biological sample is selected from a group consisting of tissue, blood, and cells, saliva, and/or cerebrospinal fluid (CSF).

11. The method of claim 8, wherein the CD44-modulating polypeptide is a polypeptide comprising SEQ ID NO:1 or SEQ ID NO:2.

12. The method of any one of claims 1-11, wherein the cancer is selected from a group consisting of ovarian cancer, breast cancer, colorectal cancer, prostate cancer, head and neck cancer, endometrial cancer, primary peritoneal cancer, liver cancer, glioblastoma, or a combination thereof.

13. The method of any one of claims 1-11 , wherein the cancer is resistant or refractory to treatment with chemo-, immuno-, gene, and/or radiation therapy.

14. The method of any one of claims 1-13, wherein the method further comprises administering a standard-of-care therapy, an anti-cancer agent, and/or radiation therapy.

15. The method of claim 14, wherein the anti-cancer agent is selected from the group consisting of avastin, paclitaxel, paclitaxel analogues, docetaxel, cabazitaxel, doxorubicin, a checkpoint inhibitor, methotrexate, cisplatin, oxaliplatin, and carboplatin.

16. A method of creating a patient cohort of one or more patients from a group of patients having a cancer, said method comprising: (a) obtaining p53 status in a biological sample obtained from each patient, p53 status being selected from: wild type, non-null, and null; (b) obtaining status of at least one additional marker; and (c) eliminating patients from the group who have p53 null status and a particular status of the at least one additional marker, wherein remaining patients in the group form a patient cohort for administering one or a combination of therapeutic compositions or therapeutic interventions for treating or ameliorating said cancer.

17. The method of claim 16, wherein the at least one additional marker is PARPi exposure status, wherein patients with a PARPi exposure status of PARPi exposed are eliminated from the group.

18. The method of claim 16, wherein the at least one additional marker comprises one or a combination of: PARPi exposure status, BRCA status, HRD status, soluble CD44 level status, PD-L1 level status, and line of therapy.

19. A method of creating a patient cohort of one or more patients from a group of patients having a cancer, said method comprising: (a) obtaining status of at least one marker; and (b) eliminating patients from the group who have a particular status of the at least one additional marker, wherein remaining patients in the group form a patient cohort for administering one or a combination of therapeutic compositions or therapeutic interventions for treating or ameliorating said cancer.

20. The method of claim 19, wherein the at least one marker is PARPi exposure status, wherein patients with a PARPi exposure status of PARPi exposed are eliminated from the group.

21. The method of claim 19, wherein the at least one marker comprises p53 status and PARPi exposure status.

22. The method of claim 19, wherein the at least one marker comprises one or a combination of: PARPi exposure status, p53 status, BRCA status, HRD status, soluble CD44 level status, PD-L1 level status, and line of therapy.

23. A method of treating a cancer or a tumor, or inhibiting progression or metastasis of a cancer or a tumor in a patient in need thereof, said method comprising: (a) obtaining status of at least one marker; and (b) administering one or a combination of therapeutic compositions or therapeutic interventions to the patient if the patient has a particular status of the at least one marker, wherein the one or the combination of therapeutic compositions or therapeutic interventions treats the cancer or tumor, inhibits progression of the cancer or tumor, or inhibits metastasis of the cancer or tumor.

24. A method of creating a patient cohort of one or more patients from a group of patients having a cancer, said method comprising: (a) obtaining status of at least one marker; and (b) selecting patients from the group who have a particular status of the at least one marker to create a patient cohort, the cohort is for administering one or a combination of therapeutic compositions or therapeutic interventions for treating or ameliorating said cancer.

25. The method of any of claims 23-24, wherein the at least one marker comprises p53 status, p53 status being selected from: wild type, non-null, and null.

26. The method of any of claims 23-24, wherein the at least one marker comprises PARPi exposure status, BRCA status, HRD status, soluble CD44 level status, PD-L1 level status, line of therapy, or a combination thereof.

27. A method of treating a cancer or a tumor, or inhibiting progression or metastasis of a cancer or a tumor in a patient in need thereof, said method comprising: (a) obtaining status of PARPi exposure, wherein PARPi exposure status is selected from PARPi exposed or PARPi naive; and (b) administering one or a combination of therapeutic compositions or therapeutic interventions to the patient if the patient has a PARPi naive status, wherein the one or the combination of therapeutic compositions or therapeutic interventions treats the cancer or tumor, inhibits progression of the cancer or tumor, or inhibits metastasis of the cancer or tumor.

28. A method of creating a patient cohort of one or more patients from a group of patients having a cancer, said method comprising: (a) obtaining status of PARPi exposure, wherein PARPi exposure status is selected from PARPi exposed or PARPi naive; and (b) selecting patients from the group who have a PARPi naive status to create a patient cohort, the cohort is for administering one or a combination of therapeutic compositions or therapeutic interventions for treating or ameliorating said cancer.

29. The method of any of claims 27-28 further comprising obtaining status of an additional marker.

30. The method of claim 29, wherein the additional marker is one or a combination of: p53 status, BRCA status, HRD status, soluble CD44 level status, PD-L1 level status, and line of therapy.

31. A method of treating an ovarian cancer or tumor, or inhibiting progression or metastasis of an ovarian cancer or a tumor in a patient in need thereof, said method comprising: (a) obtaining p53 status in a biological sample obtained from the patient, p53 status being selected from: wild type, non-null, and null; (b) obtaining status of at least one additional marker; and (c) administering one or a combination of therapeutic compositions or therapeutic interventions to the patient if the patient has either p53 wild type or p53 non-null status combined with a particular status of the at least one additional marker, wherein the one or the combination of therapeutic compositions or therapeutic interventions treats the ovarian cancer or tumor, inhibits progression of the ovarian cancer or tumor, or inhibits metastasis of the ovarian cancer or tumor.

32. A method of creating a patient cohort of one or more patients from a group of patients having an ovarian cancer, said method comprising: (a) obtaining p53 status in a biological sample obtained from each patient, p53 status being selected from: wild type, non-null, and null; (b) obtaining status of at least one additional marker; and (c) selecting patients from the group who have either p53 wild type or p53 non-null status combined with a particular status of the at least one additional marker to create a patient cohort, the cohort is for administering one or a combination of therapeutic compositions or therapeutic interventions for treating or ameliorating said ovarian cancer.

33. The method of claim 32 further comprising administering the one or the combination of therapeutic compositions or therapeutic interventions for treating or ameliorating said cancer.

34. The method of any of claims 31-32, wherein the at least one additional marker comprises PARPi exposure status, wherein PARPi exposure status is selected from PARPi exposed or PARPi naive.

35. The method of any of claims 31-32, wherein the at least one additional marker comprises BRCA status, wherein BRCA status is selected from one or a combination of: BRCA1 positive and BRCA1 negative, BRCA1 ambiguous, BRCA2 positive, BRCA2 negative, and BRCA2 ambiguous.

36. The method of any of claims 31-32, wherein the at least one additional marker comprises HRD status, wherein HRD status is selected from HRD positive, HRD negative, and HRD unknown.

37. The method of any of claims 31-32, wherein the at least one additional marker is soluble CD44 level status.

38. The method of any of claims 31-32, wherein the at least one additional marker is PD-L1 level status.

39. The method of any of claims 31-32, wherein the at least one additional marker is line of therapy of the patient.

40. The method of claim 39, wherein the line of therapy is selected from 1^st line, 2^nd line, 3^rd, line, and 4^th line.

41. The method of any of claims 31-32, wherein the at least one additional marker is selected from: PARPi exposure status, BRCA status, HRD status, soluble CD44 level status, PD-L1 level status, and line of therapy.

42. The method of claim 31 or claim 33, wherein the one or a combination of therapeutic compositions or therapeutic interventions comprises SPL-108.

43. The method of any of claims 31 or 33-41, wherein the one or a combination of therapeutic compositions or therapeutic interventions comprises SPL-108, a variant of SPL-108, a CD44-modulating polypeptide, a STAT3 inhibitor, a PD-L1 inhibitor, or a combination thereof.

44. The method of any one of claims 31-43, wherein the biological sample is selected from a group consisting of tissue, blood, and cells, saliva, and/or cerebrospinal fluid (CSF).

45. The method of claim 43, wherein the CD44-modulating polypeptide is a polypeptide comprising SEQ ID NO:1 or SEQ ID NO:2.

46. The method of any one of claims 31-45, wherein the ovarian cancer is resistant or refractory to treatment with chemo-, immuno-, gene, and/or radiation therapy.

47. The method of any one of claims 31-46, wherein the method further comprises administering a standard-of-care therapy, an anti-cancer agent, and/or radiation therapy.

48. A method of creating a patient cohort of one or more patients from a group of patients having an ovarian cancer, said method comprising: (a) obtaining p53 status in a biological sample obtained from each patient, p53 status being selected from: wild type, non-null, and null; (b) obtaining status of at least one additional marker; and (c) eliminating patients from the group who have p53 null status and a particular status of the at least one additional marker, wherein remaining patients in the group form a patient cohort for administering one or a combination of therapeutic compositions or therapeutic interventions for treating or ameliorating said ovarian cancer.

49. The method of claim 48, wherein the at least one additional marker comprises one or a combination of: PARPi exposure status, BRCA status, HRD status, soluble CD44 level status, PD-L1 level status, and line of therapy.

50. A method of creating a patient cohort of one or more patients from a group of patients having an ovarian cancer, said method comprising: (a) obtaining status of at least one marker; and (b) eliminating patients from the group who have a particular status of the at least one additional marker, wherein remaining patients in the group form a patient cohort for administering one or a combination of therapeutic compositions or therapeutic interventions for treating or ameliorating said ovarian cancer.

51. The method of claim 50, wherein the at least one marker comprises one or a combination of: PARPi exposure status, p53 status, BRCA status, HRD status, soluble CD44 level status, PD-L1 level status, and line of therapy.

52. A method of treating an ovarian cancer or tumor, or inhibiting progression or metastasis of an ovarian cancer or a tumor in a patient in need thereof, said method comprising: (a) obtaining p53 status in a biological sample obtained from the patient, p53 status being selected from: wild type, non-null, and null; (b) obtaining status of PARPi exposure, wherein PARPi exposure status is selected from PARPi exposed or PARPi naive; and (c) administering one or a combination of therapeutic compositions or therapeutic interventions to the patient if the patient has either p53 wild type or p53 non-null status combined with a PARPi naive status, wherein the one or the combination of therapeutic compositions or therapeutic interventions treats the ovarian cancer or tumor, inhibits progression of the ovarian cancer or tumor, or inhibits metastasis of the ovarian cancer or tumor.

53. A method of treating an ovarian cancer or tumor, or inhibiting progression or metastasis of an ovarian cancer or a tumor in a patient in need thereof, said method comprising: (a) obtaining p53 status in a biological sample obtained from the patient, p53 status being selected from: wild type, non-null, and null; (b) obtaining status of PARPi exposure, wherein PARPi exposure status is selected from PARPi exposed or PARPi naive; and (c) administering SPL-8 to the patient if the patient has either p53 wild type or p53 non-null status combined with a PARPi naive status, wherein SPL-8 treats the ovarian cancer or tumor, inhibits progression of the ovarian cancer or tumor, or inhibits metastasis of the ovarian cancer or tumor.

54. A method of treating an ovarian cancer or a tumor, or inhibiting progression or metastasis of an ovarian cancer or a tumor in a patient in need thereof, said method comprising: (a) obtaining status of PARPi exposure, wherein PARPi exposure status is selected from PARPi exposed or PARPi naive; and (b) administering one or a combination of therapeutic compositions or therapeutic interventions to the patient if the patient has a PARPi naive status, wherein the one or the combination of therapeutic compositions or therapeutic interventions treats the cancer or tumor, inhibits progression of the cancer or tumor, or inhibits metastasis of the ovarian cancer or tumor. A method of creating a patient cohort of one or more patients from a group of patients having an ovarian cancer, said method comprising: (a) obtaining status of PARPi exposure, wherein PARPi exposure status is selected from PARPi exposed or PARPi naive; and (b) selecting patients from the group who have a PARPi naive status to create a patient cohort, the cohort is for administering one or a combination of therapeutic compositions or therapeutic interventions for treating or ameliorating said ovarian cancer.