Afshin Dowlati, PhD

Dr. Dowlati attended the University of Liege School of Medicine and after completing an internal medicine residency there in 1996, came to Case Western Reserve University School of Medicine for an internal medicine residency and a fellowship in hematology and oncology. He joined the Case Comprehensive Cancer Center in 2000 and became Co-Leader of the Developmental Therapeutics Program in 2007.

 


My expertise lies in both the biology and clinical management of thoracic malignancies. From a clinical standpoint, I have led the thoracic program at Case Western Reserve University since 2000. My research is focused on the translational aspects of target validation and drug development and I am uniquely positioned to perform preclinical studies of novel drugs in cancer models with an eventual goal of taking them into the clinic. A major effort of my research lab is to identify novel therapeutics for small cell lung cancer (SCLC). There has been little progress in the clinical management of this disease over the last three decades, due largely to our limited knowledge about the underlying mechanisms driving this malignancy. We have built up a research infrastructure to study this disease, the foundation of this being a retrospective clinical-pathologic database on all SCLC patients treated at our medical center over the last 15+ years, which now numbers >800 patients. We have added genomic and transcriptomic sequencing results to this database, and recently surpassed 100 patients with genomic data. This allows us to determine which genomic mutations are the most clinically significant, in terms of both survival and chemo-response. We intend to use cell line and mouse models of SCLC to study the role of genomic mutations in this disease and to generate preclinical data to support future clinical trial applications. To help achieve progress in this cancer, we are founding members of an SCLC consortium whose task is to advance our understanding and treatment of this malignancy. Most recently we started a new research branch to define the molecular drivers of response to immune checkpoint blockade in SCLC.
Activation of tyrosine kinase receptors plays a major role in thoracic cancer and leads to downstream activation of the JAK-STAT pathway, particularly STAT3. We have found, however, that an alternative pathway for STAT3 activation in cancer is by down-regulating PIAS3, an endogenous inhibitor of activated STAT3. This is particularly true for mesothelioma and squamous cell lung cancer. Given the limited therapeutic options for these malignancies, we are focused on determining 1) the mechanism of PIAS3 down-regulation in thoracic cancer, and 2) ways to increase the expression of endogenous PIAS3. Our approach is innovative in that it seeks to activate a tumor suppressor of STAT3, rather than inhibit oncogenic STAT3 directly, which has proven problematic.