José Baselga, MD, PhD
Physician in Chief
Memorial Sloan-Kettering Cancer Center
New York, New York
Member, Human Oncology and Pathogenesis Program
Attending, Department of Medicine
2013-2014 BCRF Project:
(The Westchester Women's Award)
The rationale behind the development of inhibitors of the PI3K p110α subunit is the potential activity of these agents in tumors with mutations in the PIK3CA gene together with a wide therapeutic window due to their specificity. As a matter of fact, the first clinical data showed an unprecedented success in term of tumor response. However, even those patients experiencing tumor shrinkage eventually relapse and become refractory to the therapy. In 2013-2014, Dr. Baselga plans to tackle this problem by identifying both determinants of intrinsic sensitivity and possible mechanisms of resistance to p110α inhibitors, with the common objective of identifying the patients who are more likely to respond to this therapy. He and colleagues have strong evidence that PTEN loss of expression may be an important cause of both intrinsic and acquired resistance to p110α inhibitors. Moreover, they discovered that a number of responding patients have tumors with two different mutations in PIK3CA, an occurrence considered relatively rare. Dr. Baselga hypothesizes that this subpopulation of patients is hypersensitive to p110α inhibitors and plans to test his hypothesis by using both in vitro and in vivo models. Finally, due to preliminary data obtained from multiple screenings performed in his laboratory, Dr. Baselga’s team speculates that activation of kinases -- normally thought to have a marginal role in breast tumor homeostasis -- may enter into play to compensate drug-induced inhibition of the PI3K pathway. In particular, Dr. Baselga plans to investigate the role of kinases that can activate shared Akt-downstream effectors in an Akt-dependent manner.
Recent advances in the therapy of HER2 positive (HER2+) tumors include the clinical activity of new anti-HER2 agents in patients resistant to trastuzumab (Herceptin®), and the observation that dual HER2 blockade (the combined administration of anti-HER2 agents with partially non-overlapping mechanisms of action) may be superior to single agent anti-HER2 therapy. While these new agents and approaches are promising, the eventual development of clinical resistance remains a significant problem. The main aims of Dr. Baselga’s research are to discover new mechanisms of resistance to anti-HER2 therapy (trastuzumab or Herceptin® and lapatinib or Tykerb®) and to study the combinations of new agents that counteract the insurgence of such resistance.
Thanks to the establishment and characterization of novel preclinical models of anti-HER2 resistance, Dr. Baselga and his team have identified a number of genes that may be involved in reducing the anti-tumoral effects of trastuzumab, lapatinib or the combination of both. Importantly, they have also started the collection and analysis of samples from HER2+ breast cancer patients who initially responded but eventually relapsed on anti-HER2 therapy. Data obtained from these specimens will be matched with their laboratory findings, aiming to uncover genuine and clinically relevant mechanisms of anti-HER2 resistance.
Moreover, Dr. Baselga’s team has demonstrated that PI3K inhibition, together with lapatinib, has very promising anti-tumor activity in tumors intrinsically resistant to anti-HER2 therapy, without signs of significant toxicity. This finding was published in 2012 in the Clinical Cancer Research journal. This research will help to advance understanding aimed at better and safer ways to prevent, delay or overcome the insurgence of resistance to anti-HER2 therapy.
During the first six months of this research, Dr. Baselga’s team confirmed that loss of PTEN expression is sufficient to limit the activity of PI3K p110α inhibitors. This data would confirm that a possible mechanism of resistance to these compounds is the reactivation of the AKT/mTOR pathway due to engagement of other subunits of PI3K, such as p110β. As a matter of fact, the use of molecules that target this subunit can revert this phenotype.
The researchers also confirmed that, at least in one case, two mutations of PIK3CA can subsist in the same allele and act additively to activate the AKT/mTOR pathway. Finally, they identified PDK1 as a possible player in limiting the sensitivity to p110α inhibitors. Co-suppression of p110α and PDK1 results in synergistic cell growth inhibition in cells intrinsically resistant to p110α inhibitors.
José Baselga, MD, PhD has published over 300 peer-reviewed articles, in addition to over 400 abstracts and book chapters. His research interests are in Clinical Breast Cancer and in Translational and Early Clinical Research in the area of Growth Factor Receptors and Downstream Molecules as Targets for Breast Cancer Therapy. He conducted the initial clinical trials with the monoclonal antibodies cetuximab and trastuzumab. In addition, he has been involved in the clinical development of several new agents including: gefitinib, erlotinib, lapatinib, pertuzumab, m-TOR, PI3K, TGF, SRC, Insulin-like Growth Factor Receptor Inhibitors and a variety of anti-angiogenic agents. His main focus in the laboratory and in the clinic is the area of novel anti-HER2 agents, in the identification of mechanisms of resistance to anti-HER2 agents and therapeutic approaches to target the PI3K pathway.
Dr. Baselga served as President of the European Society of Medical Oncology (ESMO) in 2008-2009. He is a member of several Committees of the American Association for Cancer Research (AACR) and a member of the AACR Research Council and the AACR Board of Directors; a past member of the Board of Directors of the American Society of Clinical Oncology (ASCO), a past member of the Board of Directors of the European Organization of Research on Treatment of Cancer (EORTC); and a member of the Scientific Advisory Committee of the Ludwig Institute for Cancer Research.
Dr. Baselga has received a number of awards including a Young Investigator Award from ASCO (1992), a Career Development Award from ASCO (1994), a Brystol-Myers Squibb Unrestricted Cancer Grant Award (2002-2006), an Honorary Membership Award from The European Society for Therapeutic Radiology and Oncology (ESTRO) (2004); the Waun Ki Hong Visiting Professorship at U.T.M.D. Anderson Cancer Center in Houston, TX (2002); named Distinguished Alumnus from Memorial Sloan Kettering Cancer Center, NY (2004); Elected Member of the American Society of Clinical Investigation (2004); Annual Award from ESMO (2005); American- Italian Cancer Foundation (AICF) Prize for Scientific Excellence in Medicine (2007); AACR-Rosenthal Family Foundation Award (2008); and King James I Award (2008)
Dr. Baselga received his medical degree from the Universidad Autonoma of Barcelona in 1982. He did his Internal Medicine Residency at both Vall d'Hebron University Hospital in Barcelona, Spain and the State University of New York in the US. He completed a fellowship in Medical Oncology at Memorial Sloan-Kettering Cancer Center in New York and subsequently stayed on as a faculty member of the Breast Medicine Service at Memorial Sloan-Kettering until 1996 when he returned to Spain.
From 2010-2012, Dr. Baselga was Chief and Bruce A. Chabner Chair of the Division of Hematology/Oncology at Massachusetts General Hospital (MGH), Associate Director of the MGH Cancer Center, and Professor of Medicine at Harvard Medical School. In 2011, Dr. Baselga was also appointed Associate Director of Clinical Services at Dana-Farber/Harvard Cancer Center.
Prior to MGH, Dr. Baselga was the chairman of the Medical Oncology Service and the founding director of the Vall d'Hebron Institute of Oncology established in 2007 at the Vall d'Hebron University Hospital in Barcelona, Spain. He was also a Professor of Medicine at the Universidad Autonoma de Barcelona. Dr. Baselga holds the position of Scientific Chairman of SOLTI, the Spanish Breast Cancer Cooperative Group. He is a member of the Editorial Boards of Cancer Cell, Journal of Clinical Oncology, Clinical Cancer Research, and Annals of Oncology.
In September 2012, Dr. Baselga was named Physician-in-Chief of Memorial Hospital, part of Memorial Sloan-Kettering Cancer Center (MSKCC) in New York, and will direct the clinical component of MSKCC and lead its team of 834 attending physicians.