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.
Dr. Dowlati’s lab is interested in the biology and clinical management of thoracic malignancies, with particular emphasis on translational aspects of drug development. His focus is small cell lung cancer (SCLC), which comprises ~15% of all lung cancers. SCLC is typically diagnosed after the disease has metastasized and resistance to ensuing chemotherapy rapidly develops, leading to low patient survival. Unlike non-small cell lung cancer (NSCLC), which comprises the majority of lung cancers, molecular targeted agents have all failed to improve survival of SCLC patients. This failure can be attributed, in part, to a diverse array of mutations that may drive SCLC growth and proliferation. In an effort to build up a research infrastructure to study this disease we have built a retrospective clinical-pathologic database on all SCLC patients treated at our medical center that now numbers over 650 patient entries. Recently we have added the results of both whole exome and targeted exome sequencing to this dataset that is now approaching 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 lines and PDX models of SCLC to study the role of genomic mutations in this disease and to generate preclinical data to support future clinical trial applications. In this regard, we are part of a newly established SCLC consortium (https://www.mskcc.org/research-programs/nci-small-cell-lung-cancer-consortium), which will facilitate the exchange of ideas and research materials and lead to a more rapid understanding of this disease.
Although recent advances in molecular targeting have discovered novel therapeutics for the treatment of NSCLC, such as agents targeting the epidermal growth factor receptor (EGFR) and checkpoint inhibitors, these agents unfortunately work in only select patients. Thus, it remains critical to develop new therapeutic strategies in NSCLC as well. 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 choices for these malignancies, we are focused on determining the mechanism of PIAS3 down-regulation in thoracic cancer and 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.
- De S, Lindner DJ, Coleman C, Wildey G, Dowlati A, Stark GR. The FACT inhibitor CBL0137 synergizes with cisplatin in small cell lung cancer by increasing NOTCH1 expression and targeting tumor-initiating cells. Cancer Res 78:2396-2406, 2018. PMID: 29440145
- Ardeshir-Larijani F, Bhateja P, Lipka MB, Sharma N, Fu P, Dowlati A. KMT2D Mutation Is Associated With Poor Prognosis in Non-Small-Cell Lung Cancer. Clin Lung Cancer 19:e489-e501, 2018. PMID: 29627316
- McColl K, Wildey G, Sakre N, Lipka MB, Behtaj M, Kresak A, Chen Y, Yang M, Velcheti V, Fu P, Dowlati A. Reciprocal expression of INSM1 and YAP1 defines subgroups in small cell lung cancer. Oncotarget 8:73745-73756, 2017. PMID: 29088741
- Gardner EE, Lok BH, Schneeberger VE, Desmeules P, Miles LA, Arnold PK, Ni A, Khodos I, de Stanchina E, Nguyen T, Sage J, Campbell JE, Ribich S, Rekhtman N, Dowlati A, Massion PP, Rudin CM, Poirier JT. Chemosensitive relapse in small cell lung cancer proceeds through an EZH2-SLFN11 axis. Cancer Cell 31:286-299, 2017. PMID: 28196596
- Sakre N, Wildey G, Behtaj M, Kresak A, Yang M, Fu P, Dowlati A. RICTOR amplification identifies a subgroup in small cell lung cancer and predicts response to drugs targeting mTOR. Oncotarget 8:5992-6002, 2017. PMID: 27863413
- DowlatiA, LipkaMB, McCollK, DabirS, BehtajM, KresakA, MironA, YangM, SharmaN, Fu P, WildeyG. Clinical correlation of extensive-stage small cell lung cancer genomics. Annals Oncol 27:642-647, 2016. PMID: 26802149
- Saunders LR, Bankovich AJ, Anderson WC,…Dowlati A, et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med 7:302ra136, 2015. PMID: 26311731
- Dabir S, Kluge A, Kresak A, Yang M, Fu P, Gröner B, Wildey G, Dowlati A. Low PIAS3 expression in malignant mesothelioma is associated with increased STAT3 activation and poor patient survival. Clin Can Res 20:5124-5132, 2014. PMID: 25124686