DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Posted November 13, 2020

Lung cancers account for over 18% of all cancer-related deaths worldwide, more than any other cancer type (Ref PMID: 30207593). Solving the large and complex problem of lung cancer requires a coordinated global effort to bring together resources and innovative approaches. Fundamental to this effort is the need to attract and retain pioneering basic and clinical investigators to focus their research in the field of lung cancer. Beginning in fiscal year 2013 (FY13), the Lung Cancer Research Program (LCRP) deployed the Career Development Award (CDA) to support early-career, independent investigators doing impactful research. The CDA provides these investigators with funding to tackle new questions in lung cancer, but equally importantly, also focuses on the professional development of the investigator under the mentorship of an experienced lung cancer researcher. The ultimate goal of the LCRP’s CDA is to launch successful and impactful careers in the field of lung cancer research. 

FY19 CDA Investigators: 

Johnathan Lehman, M.D., Ph.d., Vanderbilt University Medical Center
Dr. Jonathan Lehman

Johnathan Lehman, M.D., Ph.D., Vanderbilt University Medical Center

Dr. Jonathan Lehman is a practicing medical thoracic oncologist at the Department of Veterans Affairs in Nashville, TN, and at Vanderbilt University Medical Center. He conducts his research in the laboratory at the Department of Veterans Affairs under the mentorship of Dr. Pierre Massion. Dr. Lehman’s current research focuses on small cell lung carcinoma (SCLC), the most aggressive subtype of lung cancer, and is driven by his clinical experience with Veterans who are disproportionately afflicted by the disease. SCLC is particularly devastating because most tumors develop metastatic recurrence despite initial response to therapeutic intervention. Recently, Dr. Lehman described distinct neuroendocrine survival signaling in SCLC and developed a novel single cell mass cytometry panel that can identify the expression of more than 40 individual proteins to cluster subpopulations of cells within a large number of tumor cells. Dr. Lehman’s CDA-supported work builds on these advances to identify and characterize subpopulations of SCLC cells with stem cell-like properties from patient-derived xenografts during cancer treatment. Additional studies will determine whether manipulating the Hedgehog or Wnt pathways, known to play a role in SCLC pathology, alters the growth dynamics of these unique subpopulations of SCLC tumors. This work will better define therapy-resistant SCLC subpopulations and provide potential new targets for therapeutic development to improve long-term management of the disease. 

Link:
Public and Technical Abstracts: Population Subtyping and Chemotherapy Response in Primary Small Cell Lung Carcinoma and Patient-Derived Xenografts

Lingtao Jin, Ph.D., University of Florida
Dr. Lingtao Jin

Lingtao Jin, Ph.D., University of Florida

Dr. Lingtao Jin, an Assistant Professor at the University of Florida, has a stated goal of establishing a vigorous research program committed to studying drug resistance in lung cancer. Dr. Jin recently identified microtubule-associated serine/threonine kinase 1 (MAST1) as a mediator of cisplatin resistance in non-small cell lung carcinoma (NSCLC). Additionally, preliminary work in his laboratory determined that MAST1 depletion in a unique subtype of SCLC (ASCL1-high SCLC) sensitizes these tumor cells to cisplatin. Under the dual mentorship of Dr. Frederic J. Kaye and Dr. Maria Zajac-Kaye, Dr. Jin proposes to elucidate the role that MAST1 plays in inducing platinum resistance in ASCL1-high SCLC. Specifically, the recent identification of polo-like kinase 1 (PLK1) as a MAST1 binding partner will be characterized to determine whether PLK1 activation by MAST1 contributes to platinum resistance. Secondarily, Dr. Jin will examine whether dual treatment of ASCL1-high SCLC with cisplatin and the MAST1 kinase inhibitor, lestaurtinib, may exert a synergistic effect in vitro and in patient-derived xenografts. This work will provide novel insights into the problem of therapy resistance in SCLC and lay the foundation for nearly immediate clinical evaluation of a dual therapeutic strategy with clinically verified compounds to impact patient lives.

Link:
Public and Technical Abstracts: Protein Kinase Signaling in Cisplatin-Resistant ASCL1-High SCLC

Tullia C. Bruno, Ph.D., University of Pittsburgh
Dr. Tullia C. Bruno

Tullia C. Bruno, Ph.D., University of Pittsburgh

Dr. Tullia C. Bruno, currently an Assistant Professor at the University of Pittsburgh’s Hillman Cancer Center, has devoted the past decade to becoming an expert in tumor immunology with an emphasis in evaluating the immune response in patient tumors. Under the dual mentorship of Dr. James DeGregori at the University of Colorado, Denver, and Dr. James Herman at the University of Pittsburgh, Dr. Bruno hopes to improve the efficacy of immunotherapies in lung cancer by targeting B cells. Specifically, she hypothesizes that B cells help generate long-term immune responses to tumor antigens by educating CD4+ T cells in tumor-localized tertiary lymphoid structures (TLS) and producing tumor-specific antibodies. Dr. Bruno will evaluate the systemic, B cell-specific immune signature in patients at high risk for lung cancer and use the signature to develop a non-invasive screening procedure to accurately predict progression to lung cancer. These results will improve our understanding of the adaptive immune response in the progression to lung cancer and may improve early screening modalities for patients at high risk for lung cancer development.

Link:
Public and Technical Abstracts: An Evaluation of B Cellsand Tertiary Lymphoid Structures in Lung Cancer Development

Mehdi, Alilou, Ph.D., Case Western Reserve University
Dr. Mehdi Alilou

Mehdi Alilou, Ph.D., Case Western Reserve University

As a Research Assistant Professor at Case Western Reserve University (CWRU), Dr. Mehdi Alilou has set his sights on developing an independent academic career in translational lung cancer research. Specifically, Dr. Alilou is interested in developing novel imaging biomarkers to predict patient response to immune checkpoint inhibitors, chemotherapies, and radiation therapy in lung cancer. During his postdoctoral work at CWRU, Dr. Alilou developed a non-invasive radiomics-based approach to predict and monitor NSCLC patient response to immunotherapy. This approach, termed quantitative vessel tortuosity (QVT), examines the shape, size, and convolutedness of blood vessels associated with lung nodules as captured by CT scan. With the FY19 CDA, Dr. Alilou will be co-mentored by Dr. Anant Madabhushi at CWRU and Dr. Vamsidhar Velcheti at New York University, Langone Health, and will seek to apply his QVT biomarker to predict patient response to immunotherapy in NSCLC. Initially, the QVT signatures will be refined and validated to monitor changes in individual patient nodules over time. Additionally, Dr. Alilou will begin to dissect the molecular and genetic foundation of QVT and determine what drives changes in this measurement through phenotypic and, ultimately, pathologic features of individual patient samples. This work has the potential to impact identification and clinical monitoring of NSCLC patients who will derive the most benefit from current immunotherapies. 

Link:
Public and Technical Abstracts: Quantitative Vessel Tortuosity as Biomarker for Predicting and Monitoring Response to Immunotherapy for Non-Small Cell Lung Cancer from Routine CT Scans

Timothy Robinson, M.D., Ph.D., H. Lee Moffitt Cancer Center
Dr. Timothy Robinson

Timothy Robinson, M.D., Ph.D., H. Lee Moffitt Cancer Center

Dr. Timothy Robinson is a physician scientist and radiation oncologist with a specialty in central nervous system tumors at the H. Lee Moffitt Cancer Center in Tampa. At the Moffitt Cancer Center, a large proportion of Dr. Robinson’s patients suffer from brain metastases stemming from primary lung cancers, which frequently exhibit hyper-activation of the epidermal growth factor receptor (EGFR) pathway. Under the guidance of Dr. Eric Haura and Dr. Charles Chalfant, Dr. Robinson proposes to develop a novel, alternative splice-based therapeutic approach, termed splice-ablation kinase inhibition (SAKI), to inhibit EGFR in patients with NSCLC. Hypothetically, SAKI will eliminate EGFR mutation-driven resistance to current therapeutic paradigms in NSCLC by directly suppressing the expression of the EGFR oncogene at the RNA level. Dr. Robinson’s proposed study will examine the early efficacy and toxicity of SAKI-targeted EGFR variants in mouse models of NSCLC, as well as characterize the molecular mechanism of action and specificity of these targeted variants. The success of this work would lead to an entire new class of targeted agents, based on mRNA splicing, that would be available to inhibit EGFR in dependent tumors. This study may have an even wider impact outside of lung cancer and represent an important breakthrough for other “untargetable” proteins.

Link:
Public and Technical Abstracts: Splice Ablation Kinase Inhibition (SAKI) of Receptor Tyrosine Kinases

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Last updated Friday, November 13, 2020