Targeting RAD51 and BRCA2 for cancer therapy

Background

Cancer cells are inherently unstable. That instability has been exploited as a tumor-selective cancer therapy. Cancer cells depend heavily on mechanisms, including DNA repair, that allow them to survive in the face of accumulated damage to DNA. A minority of tumours are inherently deficient in specific DNA repair mechanisms. This increases the potential for them to accumulate genetic changes that make them malignant but, paradoxically, makes them sensitive to drugs that damage DNA or inhibit DNA repair. Exploiting an inherent tumour cell deficiency to enhance the effectiveness of an anticancer drug is termed synthetic lethality. Unfortunately, synthetic lethality can be applied in only a small minority of cancers with pre-existing deficiencies. Our strategy is to expand that minority through induced synthetic lethality.

Description of the Invention

  1. Targeting RAD51: RAD51 is part of a protein complex that mediates DNA homologous recombination repair (HRR), a process vitally important in accurate, faithful reconstitution of damaged DNA to allow cell survival. We are developing IBR2 and IBR120 (small molecule synthetic alkaloids) as inhibitors of RAD51. IBR2 has tumor cell-killing capacity at low micromolar concentrations against a broad range of human tumor cell lines in vitro (lung, head and neck, stomach, breast, colon, prostate, and leukemia); is more than 300-fold less active against normal, non-tumor cells in vitro; and has good anti-tumor activity against human tumor cells grown in immunocompromised mice. IBR120 is an isoindolinyl R-enantiomer of IBR2 with more than 5-fold greater activity than IBR2. We hold exclusive, world-wide intellectual property rights to both compounds and their derivatives and have shown that IBR2 induces synthetic lethality and enhances the anti-tumor activity of a broad range of anticancer drugs with multiple modes of action (including imatinib, regorafenib, erlotinib, gefitinib, afatinib, osimertinib, and vincristine)1. IBR2 appears to have multiple targets, including RAD51, receptor tyrosine kinases, and microtubules. IBR2 and IBR120 are candidate anticancer drugs for use in combination with therapeutic anticancer cytotoxic agents.
  2. Targeting BRCA2: BRCA2 is part of the same HRR complex as RAD51. We have shown that antisense molecules targeting human BRCA2 enhance sensitivity to multiple chemotherapeutic anticancer drugs but do not enhance sensitivity to those agents in human non-tumor cells; and that antisense-mediated downregulation of BRCA2 in human tumor cells reduces the metastatic potential of those cells. Specific inhibition of BRCA2 with antisense agents, delivered by a patent-protected liposomal agent to human ovarian tumor cell xenografts in the peritoneal cavities of mice in combination with olaparib, inhibit tumor growth better than either treatment alone. We hold intellectual property rights to antisense targeting of BRCA25 and are developing antisense reagents delivered by liposomal carriers as effective anticancer agents, particularly when administered in combination with PARP inhibitors and other anticancer drugs in specific body compartments (peritoneal cavity); tumor cell spread to, and growth within, such compartments is a major contributor to mortality in ovarian, stomach, and colon cancer. BRCA2 is a therapeutic target for antisense drugs in multiple human cancers, particularly in combination with anticancer cytotoxic drugs and DNA repair-inhibiting drugs.

Keywords

cytotoxicity, inhibitor, tumour

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