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Chapter 22 - Drugs, Genomic Response Signatures, and Customized Cancer Therapy

from Section five - Chemical Genomics and Medicine

Published online by Cambridge University Press:  05 June 2012

By
Rafael Rosell ,
Teresa Moran  and
Miguel Taron
Edited by
Haian Fu
Haian Fu
Affiliation:
Emory University, Atlanta
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Summary

Aberrant signaling generated by the activation of multiple pathways occurs in cancers and contributes to their growth, invasion, and survival. For example, lung cancer–specific epidermal growth factor receptor (EGFR) mutations result in constitutive activation of EGFR and downstream signaling components, such as Akt, with dramatic response to tyrosine kinase inhibitors (TKIs) (gefitinib or erlotinib). In patients with multiple metastases, a single pill of erlotinib daily can attain a 70% response rate, a twelve-month time to progression, and a twenty-two-month median survival. In fact, in some subgroups of patients, survival has not been reached. However, results can still be further improved. A growing body of evidence suggests a role for lateral signaling or cross talk between various receptor tyrosine kinases (TKs), with subsequent signaling through multiple receptors. This knowledge can facilitate the design of new therapeutic strategies. New data on the role of prognostic markers will help both to identify the high-risk group of patients who will relapse after surgery and to customize treatment for all patients. DNA damage response is a global signaling network that – among multiple functions – facilitates DNA repair processes and thus determines the sensitivity or resistance to different cytotoxic drugs. Central to DNA damage response is the breast cancer gene 1 (BRCA1). We have examined the predictive value of the BRCA1-RAP80-Abraxas complex in patients with metastatic lung cancer who were receiving customized treatment according to BRCA1 messenger RNA (mRNA) levels. Our results indicate that a subgroup of patients with low levels of BRCA1 and RAP80 respond dramatically to cisplatin-based chemotherapy, with a time to progression of fourteen months and median survival not reached. These clinical findings require additional validation but can be even further improved with the proper combination with targeted therapy based on identification of the right molecular targets. This model of customization can be extrapolated to multiple different primary tumors.

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Chemical Genomics , pp. 301 - 319
Publisher: Cambridge University Press
Print publication year: 2012

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