After being considered as the next big thing in cancer drug development in the 1990s, PARP inhibitors were given up for dead in 2011. These compounds are now being revived as Lynparza™ (olaparib) was approved in late 2014 for the treatment of advanced ovarian cancer. A recent study published in Nature Reviews Cancer highlights potential therapeutic targets in DNA Damage Response (DDR) pathways, which need careful translational planning to avoid the long route to market that PARP Inhibitors took.
In the design of anticancer agents much time and effort has been spent on the identification of tumor specific molecular features that could be selectively targeted without affecting normal cells. However, most inherited cancers carry loss of function mutations in tumor suppressors rather than activating mutations in oncogenes, and require a radically different approach for their treatment.
In the early 1990s, drug discovery research started focusing on the identification of genotoxic compounds that could be administered to cancer cells in combination with standard chemotherapy to potentiate DNA damage and increase cell death. PARP inhibitors (PARPi) interfere with the ability of poly ADP-ribose polymerase (PARP) proteins to repair DNA single strand breaks. Several pharmaceutical companies initially proposed their use as chemopotentiators. Although promising, this strategy proved to be inapplicable in the clinic because of the high toxicity associated with combined administration of drugs.
In 2005 two parallel studies published in Nature exploited PARPi as a stand-alone treatment for cancer cases with a sensitized genetic background with pre-existing DNA repair defects. Specifically, preclinical studies on tumors carrying mutations in the BRCA1 and BRCA2 genes, that render them incapable of repairing DNA double strand breaks, showed responsiveness to PARPi treatment. Interestingly neither BRCA1, BRAC2, nor PARP1 inhibition alone is sufficient to drive tumor cell death, but the combination of both loss of functions results in synthetic lethality, suggesting an elegant, targeted, and minimally toxic way to treat patients.
Clinical Trials Cooled Down Preclinical Elation Around PARP Inhibitors
After a promising start, the transition from preclinical studies to clinical trials suffered a setback with agents like iniparib showing positive Phase II results in triple negative breast cancer, but later failing in Phase III trials. While efficacy was an issue, an important point was correct patient stratification. In a clinical trial of Lynparza, some BRCA-mutated patients were dismissed as non-responsive at the end of the trial, but actually showed an improved overall survival when compared to BRCA-positive patients from the same group.
The FDA finally approved Lynparza for the treatment of advanced ovarian cancer in late 2014 in combination with a companion diagnostic test called BRACAnalysis CDx that detects the presence of mutations in BRCA genes of relapsed ovarian cancer patients. This has reignited interest in DDR pathways and the novel agents that could emerge from targeting proteins in these processes.
A recent study published by Nature Reviews Cancer has made significant efforts in trying to bridge the gap between preclinical models and clinical trials by presenting an in-depth analysis of the function, role, and potential in cancer therapy for a collection of DDR genes. Some of the genes presented are already druggable targets under clinical investigation (e.g. ATR, PARP1, PARP2, and p53). Others, perhaps more interestingly, are genes flagged up in large-scale genomic expression data that could potentially become novel therapeutic targets (e.g. TOPBP1, PNKP, and MDM4).
What is important for any agents developed to target these genes and proteins is that they don’t face the same fate as PARPi, taking 25 years to reach the market. Utilizing the correct translational models to optimize research, and correctly stratify patients in late-stage clinical trials, should help to overcome the difficulties PARPi faced in finding their final clinical population.
At Crown Bioscience we recognize the importance of using the most predictive preclinical models available to ensure efficient and cost-effective translational research. Patient-derived xenograft (PDX) models derived directly from primary tumor tissue (our HuPrime® collection) have been shown in retrospective analyses to have >90% predictive power for tumor response to treatment. Using these patient-derived xenograft models in our precision profiling translational platforms HuTrial™, HuSignature™, and HuMark™ allow our clients to identify molecular biomarkers and genetic signatures of response before entering the clinic. Establishing a responder population before entering late-phase clinical trials allows better stratification of potential clinical trial participants, a greater likelihood of response in the clinic, and a reduced oncology drug attrition rate.
Contact us today at busdev@crownbio.com to discover how we can transform your translational oncology research, and how our new models can fit your research needs.
