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An NCI-designated Comprehensive Cancer Center, affiliated with the University of Pittsburgh School of Medicine
Research
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About one-third of the patients treated for prostate cancer opts for surgical removal of their tumors, with the remaining undergoing external beam radiation therapy (EBRT) or brachytherapy, along with androgen deprivation therapy (ADT; e.g., Leuprolide). While irradiation destroys the majority of cancerous cells, surviving ones can become senescent and resistant to treatment with increased risk of tumor reemergence. We have preliminary data that cinaciguat, a soluble guanilate cyclase (sGC) activator, decreases Bcl-2/BAX to enhance clearance and prevent reemergence of TRAMP-C1 orthotopic tumors in irradiated mouse prostates and in culture. Cinaciguat is a heme mimetic that promotes the formation of a heterodimer capable of catalyzing the formation of cGMP. Moreover, as cinaciguat acts only on heme-free sGC which accumulates in cells experiencing high levels of oxidative/nitrosative stress, such as following EBRT, it acts locally at the tumor site without systemic side effects in normal tissue where reduced sGC-Fe2+ is responsive only to nitric oxide (NO•). We are investigating the benefits of cinaciguat in: i) decreasing the detrimental effect of sGCα1 overexpression through enhanced dimerization of sGC; ii) increases cGMP levels via heme-free sGC to decrease Bcl-2 levels and promote apoptotic clearance of senescence cells (senolytic effect) and decrease NF-κβ-mediated cytokine release to dampen the SASP (senomorphic effect); iii) acting at the tumor site to limit systemic side effects; iv) obviating the need for ADT. We are using fractionated EBRT and the androgen-sensitive, luciferase-expressing, orthotopic TRAMP-C1 prostate cancer mouse model and cultured cells to characterize the therapeutic actions of cinaciguat.
The focus of Dr. Zarnegar’s laboratory is to decipher the molecular mechanisms by which Hepatocyte Growth Factor (HGF) and its receptor MET regulate hepatocyte growth and metabolism. In particular, their focus is on the regulation of hepatic glucose and fat metabolism and its implication in Fatty Liver Disease. Studies are also aimed at exploiting HGF/MET in chronic liver diseases inflicted by liver inflammation, hepatocyte degeneration and hepatitis such as NASH. Dr. Zarnegar’s laboratory also studies HGF gene mutation in human cancer such as breast, colon, and liver cancer and how to target HGF/MET axis in cancer.
Hassane Zarour, MD is a dermatologist and cancer immunologist whose research focuses on basic and translational human cancer immunology in the melanoma field. His work has led to the identification of novel melanoma MHC class II-presented epitopes that have been used in investigator-initiated trials at UPMC Hillman Cancer Center as well as in multi-center trials. Most recently, Dr. Zarour's work has contributed to elucidating the role of inhibitory receptors in promoting melanoma-induced T cell dysfunction in the tumor microenvironment. These findings led to the development of novel antibodies targeting inhibitory receptors for clinical trials. Dr. Zarour actively contributes to the design and the implementation of novel investigator-initiated trials based on laboratory findings, including two melanoma vaccine trials funded by the Cancer Research Institute and the National Cancer Institute, respectively. He is the lead scientific investigator on the Hillman Skin Cancer SPORE Project 3 that is testing the novel combination of BRAF inhibitor (BRAFi) therapy with high-dose interferon for metastatic V600E positive melanoma. He is also testing a novel combination of an anti-PD-1 antibody (MK 3475/Pembrolizumab) and PEG-interferon with grant support from an academic-industry award of the Melanoma Research Alliance.
Understanding cell behavior in native tumor microenvironments and developing new strategies to deliver therapeutics directly to tumor cells are critical in improving and extending patients’ lives. Our lab employs a quantitative approach that integrates microfluidics, systems biology modeling, and in vivo experiments to investigate the role of the tumor microenvironment on breast and ovarian cancer growth, metastasis and drug resistance. Our goal is to develop bioengineered tumor microenvironment platforms and apply them to improve understanding of tumor-stromal signaling mechanisms in order to: (1) discover biomarkers that guide new drug development and improve prognosis, (2) develop new strategies to improve existing treatment protocols and (3) engineer microfabricated tools that enable screening and personalization of cancer therapies.
The main research focuses of my lab are:
1. establishing new immunocompetent mouse models for lung cancer and utilizing them to study the therapeutic efficacy and mechanisms of novel combination of targeted therapy with immunotherapy
2. identifying new therapeutic vulnerabilities to overcome drug resistance in lung cancer
3. characterizing the organ-specific tumor immune contexture to develop immunotherapeutic strategies.
4. targeted degradation of KRAS mutants using in vivo PROTAC system.
My research primarily focuses on the epidemiology and genetics of osteoporosis. A long-term goal is to identify and characterize the genetic factors underlying osteoporosis susceptibility in different ethnic/racial groups. To achieve these goals, we have used several strategies including: population-based candidate gene methods; genome-wide admixture, linkage and association mapping; and most recently, an in vitro cellular model. This later approach is enabling us to translate discoveries made at the cellular level to the 'population' and vice versa to gain insight into the molecular genetic mechanisms underlying osteoporosis susceptibility.
Amer H. Zureikat, MD, is chief of the Division of Gastrointestinal (GI) Surgical Oncology at UPMC Hillman Cancer Center, co-director of the UPMC Hillman Cancer Center Pancreatic Cancer Program, and associate professor of surgery at the University of Pittsburgh School of Medicine. Dr. Zureikat specializes in cancers and diseases of the pancreas, stomach, liver, and duodenum, and practices state-of-the-art robotic surgery.
