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Please contect Ms. Rhea Brubaker regarding opportunities to support the Center for Vascular Biology Research:

Ms. Rhea Brubaker
Director of Development, Principal Gifts
rhea.brubaker@bidmc.harvard.edu
(617) 667-4582

dvorak
Jack Lawler, Ph.D.

Epithelial ovarian cancer is the most common cancer of the female reproductive organs, with about 230,000 new cases diagnosed each year worldwide. Approximately 140,000 women die each year from ovarian cancer, the high mortality related to the facts that 80% of patients are diagnosed with disease that has spread from the ovary to involve other areas of the body and there is a lack of effective second-line treatment options for patients who relapse. The five-year survival rate for ovarian cancer has changed very little over the last 20 years and new treatment options are urgently needed.

Ovarian cancer, like many other types of cancer, obtain nutrients and oxygen by inducing the growth of new blood vessels, a process termed angiogenesis. It is now known that shutting off angiogenesis can starve tumors by depriving them of important nutrients and oxygen, and thus represents a potentially important strategy for cancer treatment. The inner surface of blood vessels is made up of special cells called endothelial cells. Since treatments that reduce the growth of endothelial cells can shut off angiogenesis and result in tumor death, much work has been done to understand the molecules involved in this process. In that regard, a molecule known as thrombospondin-1 (TSP-1) is important because it is the first naturally occurring protein inhibitor of angiogenesis to be identified.

We have found that a portion of TSP-1 known as 3TSR interacts with another protein called CD36, which is found on the surface of endothelial cells, causing the endothelial cells to stop growing. As a result, angiogenesis is reduced and tumor cells that depend on angiogenesis die. We have also made the surprising discovery that 3TSR causes ovarian cancer cells to die through a direct inhibitory effect against the tumor itself. This effect may be due to the fact that ovarian cancer cells, like endothelial cells, express CD36. The concurrent inhibition of the growth of ovarian cancer and endothelial cells with 3TSR as a single agent, or in combination with chemotherapy, leads to a dramatic reduction in primary tumor size. In addition, it markedly reduces metastatic peritoneal tumors and fluid accumulation. The resolution of abdominal disease is important, as it is the metastatic tumors and fluid accumulation that account for the majority of sickness and mortality associated with ovarian cancer. Also, treatment with 3TSR and chemotherapy significantly prolongs the lives of experimental animals, with 80% of them showing signs of a durable cure.

Our studies represent important steps toward developing a new therapeutic option for the treatment of ovarian cancer, and we anticipate that the results of these studies will lead to human clinical trials.

Our research has been supported by grants from the National Cancer Institute and The National Heart Lung and Blood Institute of the National Institutes of Health, and a Beth Israel Deaconess Medical Center CAO Pilot Award.

parikh
Samir Parikh, M.D.

Of all acute illnesses, the global public health burden of severe systemic infections, collectively termed sepsis, may be the most pressing. Patients stay longer in hospitals and more commonly suffer long-term health impairments compared to other reasons for hospitalizations. Severe systemic infections can range from exotic pathogens such as anthrax and ebola to more common syndromes such as malaria and invasive pneumonia. Sepsis affects the entire spectrum of society—young children, healthy adults, those with chronic diseases and those without.

As highlighted by recent viral outbreaks, a critical gap exists between prevention and treatment of such infections. Much of the lethality may be attributable to powerful responses of the host that are meant to eradicate infection, but instead, inflict 'bystander' damage on the body. The Parikh laboratory studies these adverse host responses, seeking new ways to monitor and support the body's critical organ functions as infection is treated. 

We have discovered molecules made by the host that flood the lungs in response to infections. Blocking this response could stabilize respiratory function in the ICU. We have identified new pathways that may determine the resistance of key organs to abrupt shutdown during sepsis. Targeting such pathways could foster novel treatments to prevent health deterioration or hasten recovery. These discoveries have been fostered by a strong and growing network of collaborations around the world and through the application of cutting-edge technologies such as next-generation sequencing, multiplexed mass spectrometry, and functional imaging.

We have discovered molecules made by the host that flood the lungs in response to infections. Blocking this response could stabilize respiratory function in the ICU. We have identified new pathways that may determine the resistance of key organs to abrupt shutdown during sepsis. Targeting such pathways could foster novel treatments to prevent health deterioration or hasten recovery. These discoveries have been fostered by a strong and growing network of collaborations around the world and through the application of cutting-edge technologies such as next-generation sequencing, multiplexed mass spectrometry, and functional imaging.

nucera
Carmelo Nucera, M.D., Ph.D.

I am currently an Assistant Professor at Harvard Medical School, Boston, in the Division of Experimental Pathology (Department of Pathology), Beth Israel Deaconess Medical Center. I am highly driven by an intense desire to make important contributions that will directly benefit patients. I am strongly committed to make discovery aimed to immediately cure patients that are suffering with aggressive tumors. I have clinical background and intensely served patients with terrible/fatal human diseases. I am actively involved in tutoring and teaching medical students, research fellows, and clinical fellows.

My aims are to pursue research and discovery in thyroid cancer and endocrinology/metabolism, engaging in both basic science and translational/clinical research, and teaching. My laboratory includes translational projects focused on understanding metastatic/advanced thyroid cancers and developing targeted therapies, as well as on research re: ‘orphan and rare tumors’. In particular, my research program uses a powerful, multidisciplinary approach to provide new insights into the role of BRAFV600E in the angiogenic microenvironment of human metastatic thyroid cancers and role of stem cell-like pericytes linked to Long intergenic non-coding RNA (LincRNA).

The incidence of thyroid cancer is increasing more rapidly than other cancers in the US and in other countries. Anaplastic thyroid cancer (ATC) is a rare tumor, has perhaps the worst prognosis of any human cancer, with a median survival of about 3 months. ATC is resistant to standard chemotherapy, external beam radiation, and radioiodine treatment, thus new treatments are urgently needed. Outcomes could be improved with routine assessment of pro-metastatic biomarkers, which could enable earlier metastatic potential of this type of fatal thyroid cancer. The BRAFV600E mutation is the most prevalent genetic alteration (greater than 50%) in papillary thyroid cancer (PTC) and is implicated in the progression of PTC to ATC, a crucial challenge in thyroid cancer. Our previous studies demonstrated the crucial pro-metastatic role of the secreted extracellular matrix (ECM) proteins in BRAFV600E-positive PTC. My studies led to the identification of “tumor microenvironment” gene-sets (i.e. gene sets enriched in extracellular matrix genes) significantly associated with BRAFV600E-positive thyroid cancers. These molecules could represent more effective therapeutic and/or prognostic targets for thyroid cancer refractory to standard treatment, a disease for which no cure has been found. My results demonstrate that BRAFV600E affects thyroid carcinoma aggressiveness.

Furthermore, although BRAFV600E inhibitors are available, lack of response has been frequently observed.  My lab. has also generated an early intervention model of human BRAFV600E-thyroid carcinoma orthotopic mouse. We found that metastatic BRAFV600E-thyroid carcinoma cells elicit paracrine-signaling which trigger migration of pericytes, blood endothelial cells and lymphatic endothelial cells as compared to BRAFWT-thyroid carcinoma cells, and show a higher rate of invasion.  Targeting BRAFV600E using selective inhibitors significantly suppresses these aberrant functions in non-metastatic BRAFV600E-thyroid carcinoma cells but lesser in metastatic cells. We have identified copy number gain of MCL1 in metastatic BRAFV600E-PTC which are associated with resistance to BRAFV600E inhibitors treatment. Critically, we have demonstrated that combined therapy with BRAFV600E inhibitors plus BCL2/MCL1 inhibitor increases metastatic BRAFV600E-PTC cell death and ameliorates response to BRAFV600E inhibitors treatment.

We also found accumulation of VEGFR2 and increased activity of signaling pathways downstream of VEGFR2 in human thyroid cancer cells. These results offered the molecular understanding and the rationale for targeted use of sorafenib to treat thyroid cancer with low beta-TRCP protein expression levels.

My lab has also established the first BRAFWT/V600E-dependent thyroid angiogenic myopericytoma (MPC) cell culture patient-derived xenograft mouse model. MPC is a rare tumor with perivascular proliferation of pluripotent stem cell-like pericytes and clinical recurrence. My findings imply that anti-BRAFV600E agents may be useful adjuvant therapy in BRAFV600E-MPC patients which should be closely followed due to the risk for recurrence.

Overall, therapeutic strategies aimed at modulating the aggressiveness and metastasis of ATC and PTC will provide an additional perspective for new therapeutic strategies for the treatment of patients with these types of human cancers. Routine assessment of pro-metastatic biomarkers will help monitor patients undergoing targeted therapies, enable earlier metastatic potential of aggressive thyroid carcinomas, foster development of innovative therapies for refractory thyroid cancer to current treatments, and allow improved patient selection for clinical trials.

My research has been awarded by grants from the National Cancer Institute (NCI), National Institutes of Health (NIH) (R01 and R21), American Thyroid Association (ATA), ThyCa Survivors’ Association Inc., Translational Grants, Beth Israel Deaconess Medical Center CAO Pilot Award.