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Research Translation and Personalized Medicine

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Renal Cell Carcinoma

Abstract

The convergence of technological advances leading to affordable genome sequencing and an ever increasing arsenal of molecularly targeted drugs are revolutionizing oncology. These developments set the foundation for “personalized cancer therapy,” a tailored approach to cancer treatment that exploits precise knowledge about molecular alterations in tumors. This chapter contextualizes these developments and discusses their implications and practical applications for renal cancer. At the outset, two cases are presented in which information about the molecular genetics of the tumor impacted patient management. These cases illustrate the challenges and opportunities associated with this approach. Precedent was set by the identification of mutations in the VHL gene and the implication of the mTORC1 in renal cancer. Recent advances have begun to unravel the complex interplay between pVHL and mTORC1 pathways and have uncovered a role of mTORC1 in the regulation, not only of protein translation and cell growth but also of sequence-specific transcription factors and gene expression. mTOR remains an important therapeutic target, and catalytic inhibitors targeting both mTORC1 and mTORC2 as well as PI3K isoforms are under evaluation. Opportunities are emerging from cancer genome/exome sequencing studies. Mutations create vulnerabilities that can be exploited with chemical-genetic screens. Drug development may be accelerated with improved preclinical models that accurately reproduce the molecular genetics and treatment responsiveness of RCC in patients. Renewed emphasis is needed on correlative studies in clinical trials. A vision is presented for an integrated research translation program for the advancement of personalized genomic-based cancer medicine.

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Acknowledgments

I thank members of my laboratory and Dr. Kapur for providing tumor photographies. The work alluded to in this manuscript was supported by grants from NIH (KO8NS051843, R01CA129387), ACS (RSG115739), CPRIT (RP101075), Doris Duke Foundation (2007062), March of Dimes Foundation (5FY06582), and the V Foundation. J.B. is a Virginia Murchison Linthicum Endowed Scholar in Medical Research.

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Authors and Affiliations

  1. Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-9133, USA

    James Brugarolas M.D., Ph.D.

  2. Department of Developmental Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-9133, USA

    James Brugarolas M.D., Ph.D.

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  1. James Brugarolas M.D., Ph.D.
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Correspondence to James Brugarolas M.D., Ph.D. .

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Editors and Affiliations

  1. David Geffen School of Medicine at UCLA, Department of Medicine, Cedars-Sinai Medical Center, n/a, Los Angeles, 90095, California, USA

    Robert A. Figlin

  2. Lineberger Comprehensive Cancer Center, University of North Carolina, Campus Box 7295, Room 21-237, 218, Chapel Hill, 27599-7295, North Carolina, USA

    W. Kimryn Rathmell

  3. Taussig Cancer Institute, Department of Solid Tumor Oncology, Cleveland Clinic, 9500 Euclid Ave, CLEVELAND, 44195-0001, Ohio, USA

    Brian I. Rini

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This manuscript is dedicated to my father, Dr. A. Brugarolas, whose selfless dedication to his patients, curiosity, and quest to understand cancer have been an inspiration to me, and to my mother, without whom, we would not have been able to pursue our dreams.

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Brugarolas, J. (2012). Research Translation and Personalized Medicine. In: Figlin, R., Rathmell, W., Rini, B. (eds) Renal Cell Carcinoma. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-2400-0_8

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