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EP-3849310-B1 - COMBINATION CANCER THERAPIES BASED ON THE MORTALIN TARGETING COMPOUND SHETA2 AND P53 REACTIVATORS OR CDK4/6 INHIBITORS

EP3849310B1EP 3849310 B1EP3849310 B1EP 3849310B1EP-3849310-B1

Inventors

  • BENBROOK, DORIS, MANGIARACINA
  • RAMRAJ, Satish, Kumar

Dates

Publication Date
20260513
Application Date
20190912

Claims (13)

  1. A first compound which is SHetA2, and a second compound selected from PRIMA-1 met , PRIMA-1, Palbociclib, Abemaciclib, and Ribociclib, for use in a cancer treatment method comprising conjointly administering to a subject in need of such therapy a therapeutically-effective amount of the first compound and the second compound, wherein the therapeutically-effective amount yields a synergistic effect compared to an effect of the first compound alone and an effect of the second compound alone.
  2. A first compound and a second compound for use according to claim 1, wherein the cancer treatment method results in at least one of reduction of tumor size, reduction of tumor growth, inhibition of cancer metastases, cancer cell death, and inhibition of tumor recurrence.
  3. A first compound and a second compound for use according to claim 1, wherein the second compound is PRIMA-1 met or PRIMA-1.
  4. A first compound and a second compound for use according to claim 1, wherein the second compound is Palbociclib, Abemaciclib, or Ribociclib.
  5. A first compound and a second compound for use according to claim 1, wherein (i) the first compound is administered in a dose range of 1 mg/kg to 100 mg/kg, and the second compound is administered in a dose range of of 1 mg/kg to 100 mg/kg, or (ii) the first compound and the second compound are administered in a weight-to-weight ratio in a range of 50:1 to 1:50.
  6. A synergistic combination comprising a first compound which is SHetA2, and a second compound selected from PRIMA-1 met , PRIMA-1, Palbociclib, Abemaciclib, and Ribociclib, wherein the combination provides for a synergistic effect against cancer cells compared to an effect of the first compound alone and an effect of the second compound alone.
  7. A kit or commercial package, comprising a first compound which is SHetA2, and a second compound selected from PRIMA-1 met , PRIMA-1, Palbociclib, Abemaciclib, and Ribociclib, wherein the first compound and the second compound when administered conjointly provide for a synergistic effect against cancer cells compared to an effect of the first compound alone and an effect of the second compound alone.
  8. A synergistic combination according to claim 6, or a kit or commercial package according to claim 7, wherein the inhibition of cancer cells results in at least one of reduction of tumor size, reduction of tumor growth, inhibition of cancer metastases, inhibition of tumor recurrence, cancer cell death.
  9. A synergistic combination according to claim 6, or a kit or commercial package according to claim 7, wherein the second compound is PRIMA-1 met or PRIMA-1.
  10. A synergistic combination according to claim 6, or a kit or commercial package according to claim 7, wherein the second compound is Palbociclib, Abemaciclib, or Ribociclib.
  11. A synergistic combination according to claim 6, or a kit or commercial package according to claim 7, wherein (i) the first compound comprises at least one dosage in a range of 1 mg/kg to 100 mg/kg, and the second compound comprises at least one dosage in a range of 1 mg/kg to 100 mg/kg.
  12. A synergistic combination according to claim 6, or a kit or commercial package according to claim 7, comprising a dosage of the first compound and the second compound having a weight-to-weight ratio in a range of 50:1 to 1:50.
  13. A product comprising a first compound which is SHetA2, and a second compound selected from PRIMA-1 met , PRIMA-1, Palbociclib, Abemaciclib, and Ribociclib for simultaneous or sequential use in the treatment of cancer.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS The present application claims priority under 35 U.S.C. § 119(e) to U.S. Serial No. 62/730,345, filed September 12, 2018. GOVERNMENT SUPPORT This invention was made with government support under U.S. National Cancer Institute grants R01 CA196200 and R01 CA200126. The government has certain rights in the invention. BACKGROUND Despite being cancer free after primary cytoreductive surgery and platinum-based chemotherapy, approximately 70% of ovarian cancer patients will relapse after 3 years. Maintenance therapy using the FDA-approved PARP-1 inhibitor, olaparib, in BRCA mutation positive patients, or the angiogenesis inhibitor, bevacizumab, in all other patients, has been shown to prolong time to recurrence, however no improvement in overall survival was found in long term follow-up for bevacizumab or interim analysis of 21% data for olaparib. Both of these therapies have significant side effects that limit dosing and duration of treatment. Furthermore, olaparib caused an increased risk of developing secondary cancers. A rational approach for developing non-toxic maintenance therapy for ovarian cancer is to restore normal p53 activity. Mutations in the TP53 gene occur with a 96 to 100% frequency in high-grade serous ovarian cancer (HGSOC), the most common and lethal type of ovarian cancer, which can arise from fallopian tube fimbriae. Mutation or loss of p53 protein can reduce cancer therapy response. Currently p53 restoration is a target of multiple anti-cancer drug strategies, including by way of reactivation of the wild type p53 functions in missense mutant p53 (m-p53) and release of p53 from inhibitory proteins. PRIMA-1 ("p53 re-activation and induction of massive apoptosis-1") is a p53 reactivator that modifies amino acids in the m-p53 core domain to restore proper protein conformation and function. PRIMA-1MET (APR-246), a methylated analog of PRIMA-1, exhibited greater cancer cell line cytotoxicity and synergy with chemotherapy, and is undergoing clinical investigation. A first-in-human clinical trial found PRIMA-1MET to have a favorable pharmacokinetic profile, to induce wild type p53 molecular and cellular activities in tumors and to be safe at plasma levels predicted to have therapeutic effects. Currently, clinicaltrials.gov reports multiple ongoing trials evaluating PRIMA-1MET in combination with chemotherapy for several malignancies, including recurrent ovarian cancer. Another drug in development that can induce p53 activity is SHetA2 (NSC 726189), an orally bioavailable, small molecule drug that disrupts mortalin/p53 complexes in ovarian cancer cells. This drug is currently being developed for clinical trials based on its induction of apoptosis in cancer cells, while its effect on healthy cells is limited to G1 cell cycle arrest. SHetA2 also exhibited chemoprevention activity. Extensive preclinical studies conducted by the US National Cancer Institute (NCI) RAID and RAPID Programs, and others, demonstrated that SHetA2 did not cause mutagenicity, teratogenicity or toxicity, and exhibited a pharmacologic profile suitable for an oral chemoprevention agent. Peer-reviewed NCIR01 and PREVENT grants are supporting first-in-human clinical trials of SHetA2 capsules. Chun KH et al, Cancer Res. 2003 Jul 1;63(13):3826-32 teaches that SHetA2 induces apoptosis in cancer cells and that several retinoid receptor antagonists failed to prevent apoptosis induction by SHetA2. SUMMARY OF INVENTION The present invention is set out in the appended set of claims. BRIEF DESCRIPTION OF THE DRAWINGS Several embodiments of the present disclosure are hereby illustrated in the appended drawings. It is to be noted however, that the appended drawings only illustrate several typical embodiments and are therefore not intended to be considered limiting of the scope of the inventive concepts disclosed herein. The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. FIG. 1. Upregulation of mortalin expression in ovarian cancer. Representative images of mortalin immunohistochemical staining from the GOG Tissue Microarray (TMA) of ovarian cancer tumor progression.FIG. 2. Upregulation of mortalin expression in ovarian cancer epithelial cells. Comparison of average mortalin immunohistochemical positivity stain scores for epithelial cells in benign, borderline and serous tumor tissues in the GOG Tissue Microarray (TMA) of ovarian cancer tumor progression. *p ≤ 0.05, ***p ≤ 0.001.FIG. 3. Upregulation of mortalin expression in ovarian cancer. Comparison of average mortalin immunohistochemical positivity stain scores for stromal cells in benign, borderline and serous tumor tissues in the GOG Tissue Microarray (TMA) of ovarian cancer tumor progression. *p ≤ 0.05, ***p ≤ 0.001.FIG. 4. SHetA2 causes p53 accumulation in the nucleus