Exploiting RB1 Predictive Value for Cancer Therapy in the Clinical Setting: Lost in Translation

Newswise — The RB1 protein, named after the pediatric tumor retinoblastoma, was discovered in the 80s as the first tumor suppressor and, since then, its pathway has been found inactivated in most human cancers. RB1 ability to halt tumor development and growth has been mainly ascribed to its function in cell cycle regulation, which directly restrains cell division and proliferation. However, besides this canonical role, RB1 has a multitude of other functions, which profoundly affect the destiny of a cell by regulating stemness, differentiation, senescence, and even cell death. Indeed, RB1 status emerged not only as a key factor in cancer development and progression, but also as a crucial determinant of cell fate in response to various anticancer treatments. The idea of tailoring antitumoral strategies based on the patient’s RB1 status has shown potential, but its translation to the clinical setting has proved challenging.

A new commentary article, published last week in Biochemical Pharmacology, discusses many of these challenges and the importance of evaluating the status of RB1 in clinical specimens to support therapeutic decisions. The article provides a thorough overview of studies analyzing the key role of RB1 in the response to different anticancer approaches, spanning both cytotoxic (i.e. chemotherapy and radiotherapy) and cytostatic strategies (i.e. hormonal therapy) routinely used in the clinic. The authors also address the relationship of RB1 status to the effectiveness of targeted agents, such as protein kinase inhibitors including the new generation of highly selective inhibitors of the CDK4/6 cell cycle kinases, and also immunotherapeutics, which are among the most promising alternatives to conventional therapies.

“Through both canonical and non-canonical mechanisms, RB1 exerts opposite effects on the response to cytotoxic and cytostatic agents, limiting the effectiveness of cytotoxic chemotherapy and radiotherapy agents and sensitizing the cells to cytostatic hormone treatments and kinase inhibitor-based therapies,” says Paola Indovina of the Sbarro Health Research Organization at Temple University in Philadelphia (www.shro.org), first author of the article. “Moreover, the recently identified role of RB1 in immune function likely impacts the patient response to immunotherapy and other anticancer strategies.”

“Although a great amount of evidence pointed to the crucial importance of assessing RB1 status in the clinical setting, which could help to select patients who can benefit from a particular treatment, while sparing non-responders the unnecessary side effects, its predictive value is still underused mainly owing to the complexity of RB1 function and to difficulties in evaluating its functional status and context-dependent roles,” says Francesca Pentimalli, a coauthor working at the National Cancer Institute of Naples, Pascale Foundation.

“For the successful translation of RB1 predictive power in the clinical practice, it is crucial to dissect the molecular mechanisms whereby RB1, and its family members, regulate context-specific responses to the wide range of possible antitumoral strategies and to develop rigorous and standardized methods for their evaluation in clinical specimens,” says Antonio Giordano, Director and Founder of the Sbarro Health Research Organization, Professor of Pathological Anatomy at the University of Siena, Italy, who first identified one of the members of the retinoblastoma family, the RBL2 /p130 protein, and contributed to define the role of these proteins in cancer and cell cycle regulation.

About the Sbarro Health Research Organization

The Sbarro Health Research Organization (SHRO) is non-profit charity committed to funding excellence in basic genetic research to cure and diagnose cancer, cardiovascular diseases, diabetes and other chronic illnesses and to foster the training of young doctors in a spirit of professionalism and humanism. To learn more about the SHRO please visit www.shro.org


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