Posted June 28, 2022
Despite advances in therapeutic options, lung cancers still account for more cancer-related deaths worldwide than any other cancer type. 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. To help address this need, the Lung Cancer Research Program (LCRP) employs two distinct funding mechanisms, the Career Development Award (CDA) and the Idea Development Award – New Investigator (IDA-NI) option, to support early-career, independent investigators doing impactful lung cancer research.
FY20 CDA Investigators:
Dr. Viraj Sanghvi
Dr. Viraj Sanghvi is an Assistant Professor at the University of Miami’s School of Medicine who “strives to be on the forefront of cutting-edge research in lung cancer genetics and therapies.” Under the mentorship of Dr. Scott Lowe, Dr. Sanghvi’s research focuses on the uniquely high energetic demands of malignant lung tumors as an important avenue for therapeutic intervention. The high metabolic rate of tumor cells results in their production of toxic byproducts, which, if not neutralized, can negatively impact cell viability. Tumor cells therefore have harnessed a process, termed deglycation, by which some harmful metabolic intermediates are chemically altered to reduce their impact on cell viability. Dr. Sanghvi has identified two important genes, FN3K and DJ-1, that are central to the deglycation process and has shown that FN3K is critical to maintaining NRF2 oncogene-driven tumors in preclinical models of liver cancer. The LCRP’s CDA was awarded to Dr. Sanghvi to perform a comprehensive analysis of the proteins impacted by glycation specifically in lung cancer, a novel effort. The award will also enable a subsequent investigation into the role of FN3K and DJ-1 in deglycation in lung cancer in an effort to exploit these pathways as new potential therapeutic targets.
Dr. Boyko Atanassov
Dr. Boyko Atanassov, an Assistant Professor at Roswell Park Comprehensive Cancer Center, was awarded the CDA to support his desire to establish a well-funded independent research program in experimental therapeutics to bridge the gap between basic discovery and the reality of patient’s unmet needs. Specifically, Dr. Atanassov aims to focus his research program on the development of novel interventions to combat aggressive Receptor Tyrosine Kinase (RTK)-driven lung cancers. Guided by the mentorship of both Dr. Pamela Hershberger and Dr. David Goodrich, the focus of Dr. Atanassov’s project will expand on the idea that, even in TKI-resistant lung tumors, physical reduction in the cellular levels of the driving RTK reduces the growth of the cancer cells. His previous work has demonstrated that an enzyme, USP27X, is important to maintaining substantial levels of RTKs, such as EGFR, in cancer cells, thereby supporting continued cell proliferation. The LCRP award will support studies aimed at determining the mechanism by which USP27X regulates EGFR levels and evaluating the role of USP27X in the development and progression of lung cancer. If successful, Dr. Atanassov’s proposed research may illuminate new therapeutic targets in RTK-driven lung cancers, including USP27X itself, to combat the clinical problem of TKI-resistant tumors.
FY20 IDA-NI Investigators:
Dr. Triparna Sen
Dr. Triparna Sen, an Associate Professor originally at Memorial Sloan Kettering Cancer Center and now at Tisch Cancer Institute at Mount Sinai, was awarded an IDA-NI to pursue her preliminary evidence that concurrent loss of the genes KEAP1 and LKB1 (STK11) in metastatic lung adenocarcinoma is the single strongest predictor of poor patient outcomes in the clinic. Additionally, Dr. Sen has demonstrated that loss of these genes in lung adenocarcinoma cells is associated with suppression of a normal cell death process called ferroptosis, imbuing the cancer cells with an escape from death. With the FY20 award, Dr. Sen aims to determine the biological effects of KEAP1 and LKB-1 co-mutation across a panel of lung cancer cells and animal models to better understand how these tumors behave. Importantly, molecular pathways that result in suppression of ferroptosis following the co-occurring loss of KEAP1 and LKB1 will be exploited as potential new therapeutic targets for these tumors for the purpose of re-establishing the cancer’s susceptibility to a natural cell death event. Additionally, Dr. Sen’s project will seek to identify important potential biomarkers of patient response to putative ferroptosis-inducing therapies. In total, this work has the potential to positively impact the more than 10% of advanced/metastatic lung cancer patients whose tumors have concurrent KEAP1 and LKB1 loss.
Dr. Crystal Marconett
As an Assistant Professor at the University of Southern California, Dr. Crystal Marconett focuses her laboratory’s work on an unconventional tumor suppressor in lung cancer: the long non-coding RNA LINC00261. Long non-coding RNAs are an understudied class of cellular regulators with wide-ranging cellular and biological functions, including many roles in cancer development. LINC00261 has been shown to act in a tumor suppressive role in lung adenocarcinoma through an as-yet unknown mechanistic influence on DNA damage repair. Tumor cells are frequently able to subvert normal cell death mechanisms put in place when DNA becomes damaged, enabling the accumulation of mutations and progressively more aggressive disease. Dr. Marconett has proposed to understand how LINC00261 regulates a DNA repair process called nucleotide excision repair following intentional DNA damage. Further, her work will seek to determine whether LINC00261 levels in lung cancers are associated with the DNA mutational load, as well as their utility as a biomarker for patients who may benefit from immunotherapies based on the associated immunological features of patient tumors. Finally, Dr. Marconett’s study will examine the predictive value of LINC00261 expression levels as a means to identify patients who may or may not benefit from platinum-based chemotherapy, as LINC00261 has been shown to confer platinum resistance to lung cancer cells. If successful, this work will provide important insights into DNA repair and tumor cell death escape mechanisms and may prove useful as a therapeutic decision tool in the clinic.
Dr. Verline Justilien
Dr. Verline Justilien is currently an Assistant Professor at the Mayo Clinic in Jacksonville, Florida, studying the role of PKC-ι, a product of the gene PRKCI, in lung squamous cell carcinoma (LSCC), which accounts for nearly one-third of all lung cancers diagnosed. Her previous work established PKC-ι as an oncogenic driver of LSCC that is highly expressed due to amplifications within the region of chromosome 3 that contains the PRKCI gene (3q26). Further, Dr. Justilien has demonstrated that PKC-ι is vital for the maintenance of a cancer stem cell (CSC) population within LSCC through activation of the Hedgehog (Hh) pathway. With this LCRP award, Dr. Justilien seeks to determine whether co-targeting PKC-ι and the Hh pathway may alter the proliferative capacity of the CSC component within LSCC to block tumor growth in preclinical models. This work will also evaluate PRKCI gene amplification as well as biomolecules intrinsic to the PKC-ι and Hh signaling pathways for their utility as biomarkers to predict response to inhibition of these pathways for future translation to the clinic. Importantly, this project takes advantage of Food and Drug Administration-approved inhibitors for PKC-ι (Auranofin) and the Hh pathway (Sonidegib), dramatically increasing the potential translational speed of the study should Dr. Justilien’s efforts uncover a synergistic effect of combination therapy in preclinical models of LSCC.
Dr. Kris Wood
As an Associate Professor at the Duke University School of Medicine, Dr. Kris Wood has thus far established that therapeutic targeting of the oncogenic driver EGFR in non-small cell lung cancer (NSCLC) results in a specific DNA damage event that renders any surviving cancer cells dependent on a DNA repair molecule called ATM kinase. These surviving cells (residual disease) are critical for the re-emergence of tumors following initial response to therapy and drive therapy-resistant NSCLC. Dr. Wood has also found that targeting ATM kinase, in conjunction with EGFR inhibitors, leads to a much more durable response in preclinical models. To further support these findings, patients with residual disease following EGFR inhibition in the clinic exhibited high levels of ATM kinase activation, whereas patients who lacked functional ATM kinase displayed a prolonged benefit from EGFR inhibition. To extend these findings, Dr. Wood aims to further define the efficacy of co-targeting EGFR and ATM kinase in advanced preclinical models of residual EGFR mutant NSCLC. Additionally, the importance of ATM kinase in residual disease, downstream of therapies designed to target other well-known drivers of NSCLC, will be evaluated in the hope of extending combination therapy targeting ATM kinase beyond EGFR mutant tumors. If successful, Dr. Wood’s project could have immediate translational potential for EGFR mutant patients, with the possibility of a broader patient impact following results obtained in lung cancers harboring other driver mutations.
Abstract for Dr. Viraj Sanghvi
Public and Technical Abstracts: Understanding and Blocking Metabolic Deglycation in Lung Cancer
Abstract for Dr. Boyko Atanassov
Public and Technical Abstracts: Validating USP27X as a Drug Target in Lung Cancer
Abstract for Dr. Crystal Marconett
Public and Technical Abstracts: The Therapeutic Role of lncRNA-Mediated DNA Repair in Lung Cancer
Abstract for Dr. Verline Justilien
Public and Technical Abstracts: Novel Therapeutic Combination Strategies for the Treatment of Non-Small Cell Lung Carcinoma
Abstract for Dr. Kris Wood
Public and Technical Abstracts: Exploiting Target Therapy-Induced ATM Dependence in Residual Lung Tumors
Last updated Tuesday, June 28, 2022