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James W. Rocco, MD, PhD

Daniel Miller Associate Professor of Otology - Laryngology, Department of Otology and Laryngology, Harvard Medical School

Director Head and Neck research, Otolaryngology-HNS, Massachusetts Eye and Ear Infirmary

Director Head and Neck Research, Surgery, Massachusetts General Hospital

Contact Info

James Rocco
Massachusetts General Hospital
Department of Surgery - Surgical Oncology

Boston, MA, 02114
Mailstop: Jackson 904G
Phone not available.
Email not available

Assistant

Beverly Stone
Assistant
Massachusetts Eye and Ear Infirmary
Phone: 617-573-3192
Beverly_Stone@meei.harvard.edu

DF/HCC Program Affiliation

Cancer Genetics

Research Abstract

My research laboratory is located at the MGH on Jackson 9 within a joint Surgical and Medical Oncology translational core. I am supported by the Danny Miller Chair in Head and Neck Surgery through the MEEI. There are three active projects in the laboratory at this time.

1. Regulation of p16 expression in tumor suppression and senescence

The p16INK4A protein helps determine the cellular balance among tumor suppression, tissue replenishment, and senescence. It prevents inappropriate division of damaged and stressed cells by slowing the cell cycle and ultimately establishing cell-cycle arrest in cellular senescence. This tumor suppression comes at a cost to the organism, reduced regenerative potential of stem cells required for normal tissue regeneration, and risk of tissue damage from senescent cells.

The long-term objective of this project is to understand how upstream cellular signals and stresses lead to increased expression of p16. This project builds on a recent discovery by this laboratory that the C-terminal binding protein (CtBP), a co-repressor that is a target for several signaling pathways, regulates expression of p16 and senescence in primary human cells. As loss of CtBP-mediated repression increases p16 expression, it also leads to loss of the hallmark of Polycomb-based repression, the trimethylation of lysine 27 on histone H3, at the p16 promoter. Polycomb-based repression provides an epigenetic memory of which genes are repressed or expressed, a memory inherited by a cell’s progeny along differentiation pathways. The role of Polycomb-based repression of p16, however, has not been clear.

This project tests the hypothesis that the loss of Polycomb-based repression of p16 after loss of CtBP-mediated repression provides an epigenetic memory of p16-inducing stimuli, which might sensitize a cell or its progeny to later stimuli. To date our studies have focused on physical interactions of CtBP with Polycomb protein complexes and other regulatory proteins at the p16 promoter. Future studies will evaluate competing hypotheses for how loss of CtBP-mediated repression leads to loss of Polycomb-based repression and will test the significance of this epigenetic memory by examining its reversibility and its influence on responses to later p16-inducing stimuli.

In addition to helping understand how expression of p16 is regulated, with its implications for tumor biology, stem cell biology, and aging, this project will provide fundamental new information about the ways that CtBP-mediated and Polycomb-based repression can interact in gene regulation. Documenting this type of memory of past stressful stimuli will provide new insights into how gradual minor insults to tissues can lead to major consequences later. Finding ways to erase this memory could have practical importance when large numbers of primary human cells have to be grown in culture, and may ultimately lead to better ways to prevent or reverse some forms of tissue damage and aging.

2. P63 Pathway as Potential Therapeutic Targets in Head and Neck Cancer

The goal of this project is to use genomic approaches to identify new therapeutic targets in head and neck squamous cell carcinoma (HNSCC), by defining the p63 pathway in tumors in vivo. Our initial data using small inhibitory RNA (shRNA) targeted against specific p63 isoforms demonstrated that loss of p63 expression induces a p73-dependent apoptosis in HNSCC cells that overexpress ∆Np63α. We also identified the anti-apoptotic protein, Bcl-2 as a critical downstream mediator essential for cell survival after cisplatin treatment. Using a uniformly treated cohort of patients with advanced oropharyngeal squamous cell carcinoma (OPSCC) we subsequently demonstrated that elevated pretreatment Bcl-2 levels predict therapeutic resistance to concurrent platinum based chemoradiation. This study therefore defines a novel subgroup of patients who will require more aggressive or novel therapies to achieve survival rates comparable to the Bcl-2 negative cohort. Furthermore, the elevated levels of Bcl-2 found in these patients represent an attractive therapeutic target for small molecule Bcl-2 inhibitors currently under evaluation.

We have also found that pre-treatment tumor expression of the anti-apoptotic protein Bcl2 can be combined with tumor HPV status to identify groups of patients having different risks of recurrence and death following concurrent chemoradiation, a standard of care for advanced OPSCC. Bcl2 and HPV are not associated with each other, and they provide independent estimates of risk of recurrence and death. This is a particularly important advance with respect to the growing subset of OPSCC that are HPV-associated. Although HPV-associated OPSCC are known to respond better to treatment than do tumors associated with the traditional risk factors of smoking and drinking, treatment fails for a significant fraction of patients with HPV-associated tumors.

We report that pre-treatment tumor Bcl2 expression in HPV-associated tumors
distinguished a subgroup that is almost always cured after concurrent chemoradiation
Bcl2-negative, 3% recurrence) from one with a substantial risk of failure (Bcl2-positive, 24% recurrence). The association of Bcl2 expression with increased risk of recurrence also holds for HPV-negative tumors. Furthermore, the association that we found between Bcl2 expression and failure through distant metastasis both suggests presently available therapies that might improve outcome in some groups of patients and provides additional support for developing therapies based on inhibiting Bcl2 function. Our results on Bcl2 should also help inform the design of trials for treatments of HPV-related OPSCC that lead to less morbidity.

3. Phase II clinical trial of AZD2171 in unresectable Head and Neck Cancer

The majority of head and neck squamous cell carcinoma (HNSCC) patients present with advanced stage III or IV disease at diagnosis, with cure rates ranging from 30 to 55% after standard treatment strategies. Recurrent HNSCC often presents as unresectable disease for which curative treatment is seldom possible. Antiangiogenic drugs offer new hope for reducing the mortality and morbidity of these tumors by targeting blood vessels required for tumor growth and metastasis. AZD2171 (NSC 732208) is an orally available small molecule receptor tyrosine kinase inhibitor with activities against VEGF receptors 1, 2, 3, PDGFRβ, and c-kit. As a broad-spectrum inhibitor of angiogenesis, we predict a more sustained and durable response with AZD2171 than seen in prior clinical trials using more selective antiangiogenic inhibitors, where tumors may escape sustained inhibition through “switching” to alternate angiogenic pathways. Our primary study objective is to measure the clinical response to AZD2171 monotherapy. Secondary objectives include characterizing the time course of morphologic and physiologic changes in tumor vasculature during AZD2171 treatment and correlating these changes with surrogate markers, functional imaging, and gene expression in both endothelial and tumor cells. The unique accessibility of HNSCC tumors for tissue biopsy and physiologic measurements (IFP and pO2) will allow us to directly test the hypothesis that blocking VEGF signaling can normalize tumor vasculature. Confirmation of this hypothesis may open the door for future strategies based on AZD2171 to normalize the tumor microenvironment prior to the delivery of cytotoxic treatment.

Publications

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