Cell Cycle Blockade and Therapeutic Sensitization

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Cisplatin and carboplatin (Pt) are used heavily in the clinic against a variety of cancers, such as those of ovarian, non-small cell lung (NSCLC), testicular, head & neck, and bladder origin. These drugs demonstrate good activity, but in most cases, the activity is short-lived as tumors become desensitized by the onset of resistance. Several options are available to sensitize tumor cells to platinum-based therapy. Since Pt drugs interact with DNA to form DNA adducts as a mechanism of their action, inhibition of DNA repair can make tumor cells highly sensitive through persistence of the DNA adduct. Repair of these adducts by nucleotide excision repair (NER) in testicular cancers is low, which makes these cancers highly sensitive to Pt drugs and leads to about 90% cure rate. Recent data suggests that repair of these adducts is complex, and involves NER-mediated incisions that induce double strand breaks as intermediates, which are then repaired by homologous recombination (HR). The base excision repair (BER) pathway has also been implicated in cisplatin repair. Interestingly, the spectrum of Pt activity in the clinic has broadened to include triple-negative breast cancers that harbor BRCA1 mutation or low BRCA1 expression (BRCAness tumors). High sensitivity has also been observed in hereditary or low-expressing BRCA1 ovarian cancers. Sensitization from loss of BRCA1 is due to resultant HR defect, which when combined with inhibition of poly-(ADP-ribose)-polymerase (PARP) in the BER pathway by olaparib produces synthetic lethality. Thus, olaparib further augments Pt sensitivity in tumors with the BRCAness phenotype. This sensitization, however, is limited to the small number of BRCA1 patients, but in our proposal we will test the hypothesis that small molecules inducing cell cycle blockade will suppress BRCA1 expression in BRCA1-proficient ovarian and breast cancers to enhance tumor cell sensitivity to Pt drugs and PARP inhibitors. We will address this hypothesis through three specific aims: 1) Establish the relationship between cell cycle blockade and BRCA1 expression and delineate the mechanism of cell cycle blockade causing BRCA1 suppression; 2) Define downstream mechanisms downregulating BRCA1 as a result of cell cycle blockade; and 3) Identify rational combinations for synergistic activity and demonstrate proof-of- concept in xenograft/PDX systems. Several agents are reported independently to induce cell cycle arrest and we will prospectively establish the novel relationship with BRCA1 suppression utilizing pharmacologic tools to define antitumor activity, biochemical and molecular tools to define the underlying basis of cell cycle blockade and of BRCA1 suppression, and use the Bliss and Chou-Talalay mathematical models to identify synergistic combinations of cisplatin and olaparib with an optimal inducer of BRCAness. This project has the potential to sensitize cisplatin refractory cancers and also broaden the cancer base that could be treated rationally on a proven therapy-based principal of BRCA1-mediated defect in HR. There is high expectation that the studies proposed will change the trajectory of survival outcomes in large numbers of BRCA1-proficient cancers.