James W. Rocco, MD, PhD
Assistant Professor of Otology and Laryngology
Harvard Medical School
Massachusetts General Hospital Cancer Center
The The Rocco laboratory works to improve treatment of head and neck cancers. Tumors of the tonsil and the back of the throat—a region called the oropharynx—are occurring more frequently due to human papillomavirus (HPV), the virus that causes most cervical cancer. Although oropharyngeal tumors often respond to combined chemotherapy and radiation, about 2,000 people in the United States die of them every year, and those who are cured can suffer severe long-term consequences of treatment. Being able to predict outcome before treatment would help personalize therapy and identify patients who need more aggressive treatment. We have found that high tumor levels of the protein Bcl2 are related, in the laboratory, to resistance to chemotherapy and, in the clinic, to worse outcomes. In the laboratory, we are investigating whether inhibitors of Bcl2 function might provide an alternative treatment for oropharyngeal tumors that fail to respond to standard therapies. In the clinic, we are studying whether analysis of Bcl2 function in patients’ tumors improves predictions about responses to therapy.
James W. Rocco, MD, PhD
My laboratory’s studies of how cytotoxic therapy affects tumor cells has led to a promising translational application in oropharyngeal squamous cell carcinoma (OPSCC), an increasingly prevalent form of head and neck cancer associated with human papillomavirus (HPV) infection.
Laboratory studies of therapeutic targets in head and neck cancer
The platinum-based concurrent chemoradiation therapy frequently used to treat head and neck tumors acts in part through the p63/p73 network of proteins. In this network, a form of p63 called deltaNp63 prevents one form of p73 from starting a cellular program that leads to cell death. We found that cisplatin leads to loss of deltaNp63, allowing p73-driven cell death. However, some tumor cells can stay alive after cisplatin treatment if they have high levels of the antiapoptotic protein Bcl2. We are now studying whether drugs that inhibit Bcl2 function might provide complementary or alternative treatment for tumors whose high Bcl2 levels tend to oppose standard therapy.
Mechanism-based biomarkers in oropharyngeal tumors
The incidence of HPV-associated OPSCC, now over 75% of OPSCC cases and accounting for nearly half of OPSCC deaths, has increased 7.5% per year for the past two decades. The high morbidity and frequent failure of chemoradiation therapy for this increasingly prevalent disease indicate the need for improved methods to predict treatment outcome.
Extending our basic-science results to the clinic, we found that chemoradiation tends to fail in patients whose tumors have high Bcl2 expression. Notably, we found that Bcl2 and HPV status are not related to each other and provide independent estimates of treatment failure. We are currently validating these findings in a large, prospective clinical study, while applying the novel technology of BH3 profiling to examine the functional status of Bcl2 and related proteins that regulate cell death.
Regulation of p16 expression in tumor suppression and senescence
The p16INK4A protein helps prevent division of tumor-prone cells by slowing the cell cycle and inducing cellular senescence. This process costs the organism, however, by reducing the regenerative potential of stem cells required for tissue maintenance and increasing the risk of tissue damage from senescent cells. We discovered that the C-terminal binding protein (CtBP), a target of several stress-signaling pathways, regulates p16 expression through loss of Polycomb-based repression. This epigenetic memory is likely a major tumor-suppressive mechanism that is inherited by a cell’s progeny and may explain how gradual minor insults to tissues can lead to eventual growth arrest and senescence. Finding ways to reset this memory could help prevent or reverse some forms of tissue damage and aging.
Phase II clinical trial of AZD2171 in unresectable head and neck cancer
Many patients with head and neck cancer have advanced disease that recurs after treatment; recurrences usually cannot be removed surgically and are resistant to other standard therapy. Drugs that target development of blood vessels required for tumor growth and metastasis offer new hope for these patients. We are measuring clinical responses to AZD2171 (NSC 732208), an orally administered VEGFR2 inhibitor. This trial will test our prediction that AZD2171 will prevent or slow the growth of cancer by blocking the formation of new blood vessels.
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