Periodic Reporting for period 1 - TargetBRCA (To develop a new targeted therapy for the treatment of naive and PARP inhibitor-resistant BRCA1/2-mutated tumors)
Período documentado: 2022-08-01 hasta 2024-01-31
Among the many molecular mechanisms that lead to cancer development and progression, gain-of-function alterations in oncogenes (genes with potential to contribute to the development of cancer) and loss-of-function mutations in tumor suppressor genes’ (normal genes that slow down cell division or initiate cell death) function are central1. Large-scale genomic studies estimate that half of high-grade ovarian and triple negative breast cancer (TNBC) have alterations in the homologous recombination (HR)-mediated DNA repair pathway. Defects in HR, which occur mostly through mutations in BRCA1 and BRCA2 genes (BRCA1/2), correlate with sensitivity to certain types of DNA-damaging chemotherapeutics. Moreover, loss of HR causes genomic instability and hyper-dependence on alternative DNA repair mechanisms for survival, setting the stage for synthetic lethality-based targeted therapy. For instance, loss of BRCA1/2 gene function causes hypersensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi), notably due to impaired HR-mediated repair of stalled replication forks (RFs) resulting from PARP1-trapping lesions. As a result, PARPi is a proven effective treatment of HR-deficient (HRD) cancers, such as BRCA1/2-mutated breast and ovarian tumors. Although we have come a long way in the line of HRD cancer treatments, it remains a significant problem, as patients are often insensitive to treatment or become resistant to it upon continued use.
Indeed, at least 40% of HRD tumors are nonresponsive to PARPi, while about 50% of responsive cases will develop acquired resistance. This stresses the high unmet medical need for patients with no other therapeutic options. In 2020, more than 2.3m people were diagnosed with breast and ovarian cancer globally, while ~650k diagnosed patients died; a saddeningly high mortality rate that illustrates the relevance of this global challenge. Furthermore, it is evident that breast and ovarian cancers continue to pose a societal health burden as well as an economic burden worldwide. In 2020, medical costs were estimated to be about $26.2 and $6.3 billion in the United States, respectively for breast and ovarian cancers (National Cancer Institute). New therapeutic options are therefore needed to offer alternative strategies to effectively treat HRD breast and ovarian cancers, to lower incidences of therapy-resistance and to increase the chances of survival for patients.
Studies during the ERC Starting grant have revelated a new therapeutic target for the treatment of these cancers. Blocking this enzyme effectively induces cytotoxicity in PARPi-naive and -resistant HRD cancer cells while leaving healthy cells unharmed (Musiani et al. In revision, 2023). The goal of our TargetBRCA project is to develop the first-in-class inhibitors against this enzyme.
Indeed, at least 40% of HRD tumors are nonresponsive to PARPi, while about 50% of responsive cases will develop acquired resistance. This stresses the high unmet medical need for patients with no other therapeutic options. In 2020, more than 2.3m people were diagnosed with breast and ovarian cancer globally, while ~650k diagnosed patients died; a saddeningly high mortality rate that illustrates the relevance of this global challenge. Furthermore, it is evident that breast and ovarian cancers continue to pose a societal health burden as well as an economic burden worldwide. In 2020, medical costs were estimated to be about $26.2 and $6.3 billion in the United States, respectively for breast and ovarian cancers (National Cancer Institute). New therapeutic options are therefore needed to offer alternative strategies to effectively treat HRD breast and ovarian cancers, to lower incidences of therapy-resistance and to increase the chances of survival for patients.
Studies during the ERC Starting grant have revelated a new therapeutic target for the treatment of these cancers. Blocking this enzyme effectively induces cytotoxicity in PARPi-naive and -resistant HRD cancer cells while leaving healthy cells unharmed (Musiani et al. In revision, 2023). The goal of our TargetBRCA project is to develop the first-in-class inhibitors against this enzyme.
During our ERC Proof-of-Concept project TargetBRCA, we have developed an activity assay with a high robustness (Z’ >0.9) to conduct a High Throughput Screen (HTS) where we screened a library of ~250k Lead-like compounds at a concentration of 30μM to identify both ortho- and allosteric inhibitors of our drug target. From this library, we were able to identify 2590 hits (1% hit rate) and confirm 789 of them. Further work identified a first series of small molecules with great potency and some degree of specificity against our enzyme of interests. Finally, preliminary analysis revealed that these molecules are soluble.
Our data revealed an unexpected synthetic lethality with HRD, suggesting that the newly identified drug target can be a game-changing target for cancer treatment.
We are now aiming at further developing and validating the first best-in-class inhibitors developed during TargetBRCA to be used for the treatment of HRD tumors. This therapy can be synergized with other targeted agents, such as PARPi, to increase effectivity in unresponsive/resistance-acquired tumors. We will use breast and ovarian cancers, as our first lead to provide proof of concept data for the suitability of this therapy and evidence of its therapeutic effect in prominent forms of breast and ovarian cancers, thereafter, branching this approach to other HRD cancers, such as pancreatic and prostate cancer.
We are now aiming at further developing and validating the first best-in-class inhibitors developed during TargetBRCA to be used for the treatment of HRD tumors. This therapy can be synergized with other targeted agents, such as PARPi, to increase effectivity in unresponsive/resistance-acquired tumors. We will use breast and ovarian cancers, as our first lead to provide proof of concept data for the suitability of this therapy and evidence of its therapeutic effect in prominent forms of breast and ovarian cancers, thereafter, branching this approach to other HRD cancers, such as pancreatic and prostate cancer.