Clinical Pharmacology of Genotype-Directed Anticancer Therapy: Towards Rational Combination Strategies

Abstract

In the past two decades, a major paradigm shift has taken place in the field of cancer therapy. From non-specific cytotoxic chemotherapy that damages both tumor and normal cells, to more specific targeted agents directed against specific genetically mutated proteins that tumor cells rely on for their uncontrollable expansion. However, although successes have been achieved with this strategy, its major limitation lays in the extensive heterogeneity within tumors. Most tumors harbor multiple oncogenic mutations, making them less dependent on a single driver, acquired resistance may emerge through new mutations, and as many molecular signaling pathways are interconnected, inhibiting one may activate the other. The research described in this thesis mainly focused on novel anticancer agents and combination strategies to improve the anticancer efficacy of the genotype-directed treatment strategy. In this regard, we made great progress for patients with BRAF mutated (BRAFm) colorectal cancer (CRC), a patient group with a very poor prognosis and for whom no effective treatment options are available. Whereas in patients with BRAFm melanoma, pharmacological inhibition of BRAF resulted in dramatic responses and a significant survival benefit compared to standard chemotherapy, the antitumor activity of BRAF inhibitors in patients with BRAFm CRC was disappointing. Preclinical work demonstrated the presence of a negative feedback activation loop that activates the epidermal growth factor receptor (EGFR) and thereby reactivates the MAPK- and phosphoinositide 3-kinase (PI3K) signaling pathways upon BRAF inhibition in BRAF mutated CRC cells, explaining their resistance against single-agent BRAF inhibitor. Following these findings, we investigated the concept of combined BRAF plus EGFR inhibition in human patients for the first time, in multiple clinical phase I/II studies. In these studies, we demonstrated that combinations of BRAF inhibitors plus anti-EGFR antibodies are safe and tolerable, we established the recommended phase II doses, and we obtained early evidence of clinical antitumor activity, showing a promising progression-free survival benefit compared to historical data on the current standard treatment options. A second research focus of this thesis comprised rational combinations of targeted therapy and chemotherapy. Given the critical role of the Wee1 tyrosine kinase in maintaining genomic stability upon DNA damage, inhibition of Wee1 combined with DNA-damaging chemotherapy has become a promising strategy for the treatment of cancer. Because cells that lack a functional p53 protein rely on Wee1 function for DNA repair, p53-deficient tumors are particularly sensitive to Wee1 inhibition combined with chemotherapy. Following our large phase I study in which we investigated the safety of Wee1 inhibitor AZD1775 combined with different chemotherapeutic agents and established the recommended phase II doses, we conducted a proof of concept phase II study with AZD1775 plus carboplatin in patients with p53-deficient platinum-resistant ovarian cancer. The data collected in this study demonstrated encouraging efficacy as AZD1775 plus carboplatin compared favorable to first-line and second-line treatment options in this patient population. Therefore AZD1775 combined with carboplatin could improve clinical outcome in a patient population that has shown poor prognosis and very limited response to currently available treatment options.