Abstract PL07-02: Rational cancer drug development for targeted drugs.
Authors: Gaynor Richard B. 
Published: June 2012

Abstract
The discovery and the development of novel targeted agents for cancer therapeutics is rapidly evolving as a result of our improved understanding of cancer biology. Identification of the diverse genetic changes in different tumors including specific mutations that drive tumor growth is occurring at a rapid pace. This analysis coupled with a better understanding of the diverse mechanisms that lead to drug resistance may result in improved therapeutic interventions. In addition, recent data has provided new insights into identifying the diverse cell types that comprise the tumor microenvironment, characterizing the role of the immune system in both stimulating and inhibiting cancer growth and deciphering new mechanisms such as epigenetics and RNA-based silencing that are involved in tumorgenesis. These insights have provided us with new therapeutic options which have in some cases resulted in impressive clinical benefit.
Even with these advances, a number of challenges remain in order to develop more effective cancer therapeutics. These include better defining key cellular targets that drive the growth of specific tumors, identifying appropriate patients with these genetic changes so as to better tailor therapeutic interventions, discovering more efficacious agents that are able to inhibit targets while providing a reasonable margin of safety so as to allow combination with other agents, and developing novel trial designs and endpoints incorporating biomarkers in order to facilitate clinical testing of targeted therapeutics.
The use of biomarkers is critical in order to identify the key growth drivers of specific tumors and select the appropriate patients for therapy. In phase I trials, it is critical to use both pharmacokinetic and pharmacodynamic measures to establish the biologically effective dose of the drug being tested in terms of its ability to inhibit the target and alter tumor biology. Tumor biopsies and/or the use of surrogate tissues and appropriate in vitro assays are critical for this analysis. It is important to define whether a targeted agent alone will be sufficient to alter tumor growth or whether it will need to be combined with other targeted agents or chemotherapy. Preclinical data with appropriate cell lines that have been genetically characterized is essential to inform the clinical studies. Another major issue for both small and large molecule targeted therapeutics is the emergence of drug resistance. Repeat biopsies coupled with genetic analysis of tumors are important to better understand the mechanisms leading to drug resistance. This will inform the use of different therapeutic combinations or new agents to either reverse or prevent resistance.
Finally, novel clinical trials designs are being developed given the changing paradigm in cancer drug development from a cytotoxic focus to one utilizing targeted agents. Biopsy and analysis of tumor tissues is critical to characterize genetic changes in tumors and identify specific patient subgroups that may benefit from treatment with targeted agents. The I-SPY 2 and the BATTLE trials are examples of adaptively designed trials where clinical response is correlated with a patient's tumor genetic profile. The utilization of next generation sequencing and the quantitative analysis of both RNA and protein expression in tumor tissues both pre and post treatment are critical to better understand how genetic changes correlate with clinical outcomes.
As the development of novel targeted agents evolves, the regulatory landscape will also need to change. In addition to utilizing overall survival as the primary endpoint, endpoints such as progression free survival and molecular responses will become increasingly important. The use of in vitro diagnostics will be necessary to help guide therapeutic development in order to identify appropriate patients for specific therapies. As targeted agents move into earlier stages of disease treatment, appropriate statistical and correlative endpoints that predict clinical benefit will need to be utilized. Thus, as new insights allow a better understanding of the complexity of cancer biology, the discovery and clinical development of new therapeutics will also need to evolve in order to improve clinical outcomes for patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr PL07-02.