Anish Thomas, MBBS, M.D.

Small cell lung cancer (SCLC) is an exceptionally lethal cancer. Approximately 30,000 die each year from SCLC in the United States alone. The median survival of newly diagnosed patients is less than a year. There are no targetable oncogenes or molecular subtypes that inform clinical decision making and hence, patients with SCLC are treated uniformly with identical treatment regimens for all patients at diagnosis and at relapse. While advances in targeted therapies have spurred sharp reductions in mortality rates from non-small cell lung cancer (NSCLC), the most common lung cancer, there have been limited progress for SCLC for several decades now. In cancers that lack actionable oncogenes, targeting the well-defined phenotypic hallmarks could be of therapeutic benefit. One such hallmark is genomic instability, which promotes genetic diversity and thereby drives the acquisition of multiple hallmark capabilities. DNA damage resulting from unabated replication – referred to as DNA replication stress – is a major source of genomic instability. In the Thomas lab, we study replication stress and approaches to enhance it in a targeted manner in cancer cells, with the goal of improving lives of patients with SCLC. Our clinical and translational studies have 2 major research goals: 1) Exploit DNA replication stress to effectively treat SCLC and other chemo-resistant tumors and 2) Genomic characterization of SCLC, to understand the biology of treatment response and resistance, and to translate these findings into new treatment approaches.

Targeting ATR, the main transducer of replication stress
Ataxia telangiectasia and Rad3-related (ATR) is an essential kinase that senses stressed replication forks and orchestrates the multifaceted replication stress response. Selective small-molecule inhibitors of ATR entered clinical development around 2013 but had limited activity. We hypothesized that inhibition of ATR could enhance replicative damage from clinical inhibitors of DNA topoisomerase I (TOP1), a nuclear enzyme that suppresses genomic instability (Sci Trans Med 2016; DOI:10.1126/scitranslmed.aaf6282 ). In an investigator-initiated clinical trial, we combined first-in-class ATR inhibitor M6620 (berzosertib, previously VX-970) and TOP1 inhibitor topotecan. In the first published clinical trial of an ATR inhibitor, we showed that the drug combination enhanced replication stress and provided evidence of pharmacodynamic modulation of ATR activity at clinically achievable drug concentrations, while being systemically tolerable (J Clin Oncol 2018: DOI:10.1200/JCO.2017.76.6915 ).

Extending this work, we are currently investigating the anti-tumor activity berzosertib in combination with topotecan in patients with relapsed SCLC in single-arm and randomized phase II clinical trials (Clinicaltrials.gov identifier: NCT02487095, NCT03896503). In parallel, we are examining pre-treatment tumor exomes and transcriptomes to dissect responses and rationalize patient stratification for future studies. Replication stress is a common feature of cancers with activated oncogenes or absent tumor suppressors that accelerate the rate of S-phase entry and disrupt the DNA replication schedule. While replication stress itself and the mechanisms that mitigate replication stress are increasingly recognized as cancer cell-specific vulnerabilities, rational targeting of these dependencies require reliable approaches to measure replication stress and its cellular responses in patient tumors. However, measures of replication stress widely used in experimental settings are not optimized for use in large cohorts of clinical biopsy samples. We are interested in developing transcriptional profiling-based approaches to characterize replication stress at a functional network level.

Defining clinically relevant SCLC molecular subsets and identify novel vulnerabilities
Cancers that appear morphologically similar often have markedly different clinical features, respond variably to therapy, and have a range of outcomes. Tumor genomic profiling has led to the identification of previously unrecognized cancer subtypes, informed the biology and developmental origins of cancers, and have substantially transformed the care of many cancer patients. However, the identification of molecular subtypes has remained an elusive goal for SCLC. We studied SCLC detected via computed tomography screening (Chest 2018; DOI: 10.1016/j.chest.2018.07.029) and SCLC in never-smokers (Chest 2020; DOI: 10.1016/j.chest.2020.04.068) to define potentially targetable SCLC phenotypes, and found that never-smokers had unique demographic and genomic characteristics including lower tumor mutational burden, and absence of mutational signatures related to tobacco exposure.

Following up on these observations, to explore a potential inherited susceptibility to SCLC, we performed whole-exome sequencing on the germ lines of a cohort of patients with SCLC, finding that almost half the cohort carried deleterious variants in cancer-predisposing genes, including actionable variants in 10% of patients. (Sci Trans Med 2021; http://stm.sciencemag.org/cgi/rapidpdf/13/578/eabc7488?ijkey=YFX90CKLyunEA&keytype=ref&siteid=scitransmed). These findings were validated in an independent cohort of 79 patients with SCLC.  Those with pathogenic germline variants had better response to platinum-based chemotherapy, and in one patient, the genetic information was used to select a combination of chemotherapeutic agents that resulted in substantial reduction of tumor burden. Germline genotype could provide personalized treatment options for a small but important fraction of SCLC patients. Germline testing of family members of SCLC patients who harbor a cancer-predisposing germline mutation could save additional lives through screening and prophylactic measures aimed at the cancers associated with those inherited mutations. We also applying genomic approaches to circulating tumor DNA to noninvasively track SCLC burden and responses and perform research autopsies to investigate the mechanisms of cancer evolution, metastasis, and treatment resistance.

Novel approaches to leverage DNA damage response in combination therapies
While a number of potent and specific DNA damage response inhibitors (PARP, ATM, ATR, WEE1, DNA-PK and others) are approved and in development, combinations that represent the standard-of-care typically require reduced doses of chemotherapy to maintain acceptable tolerability. We have hypothesized that a dose-escalation strategy that incorporates tumor-targeted DNA-damaging chemotherapy delivery and dose scheduling of DDR inhibitors could allow administration of effective combination doses to drive durable tumor responses (Clin Cancer Res 2019; DOI: 10.1158/1078-0432.CCR-19-1089 ). In a number of ongoing clinical trials, we are investigating targeted delivery of cytotoxic agents and gapped administration of DDR inhibitors. These trials use several platforms/approaches for targeted/protracted delivery including nanoparticles (NCT02769962), PEGylation (NCT04209595), antibody drug conjugates, liposomal formulations (NCT02631733) and Hsp90-drug conjugates (NCT03221400).