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Center for Cancer Systems Biology

Pilot Projects

wUnderstanding SCLC Heterogeneity and Evolution through Analysis of Circulating Tumor Cells in Patients With Small Cell Lung Cancer

Lead By Dr. Chrisitne Lovly and Prasad Kopparapu 

Small cell lung carcinoma (SCLC) is a high-grade neuroendocrine tumor that affects ~15% of lung cancer patients and causes ~200,000 deaths annually worldwide1. This makes SCLC the 6th leading cause of cancer death by itself. Most, ~70-80% of SCLC patients present with distant metastases at first diagnosis, and 5-year overall survival remains <1% for this disease1. There is an urgent need to develop novel diagnostic and treatment strategies for SCLC patients.

There are several significant obstacles impeding the successful design and implementation of improved therapeutic strategies for patients with SCLC. First, at the time of initial diagnosis, the majority of patients already have metastatic disease. Therefore, curative surgery is rarely an option. Second, since most patients do not undergo surgical resection, the availability of tumor tissue to study SCLC is significantly limited. Third, while SCLC is initially sensitive to conventional chemotherapy, resistance to chemotherapy rapidly develops, likely due to the underlying complex heterogeneity and evolution over time within the tumor itself. An understanding of this heterogeneity at the molecular and cellular level is lacking.

The overarching goal of this project is to develop a robust and reproducible mechanism to isolate Circulating Tumor Cells (CTCs) from blood samples obtained from patients with SCLC throughout their disease course. CTCs provide a noninvasive measure of disease progression and response to therapy. CTC count after treatment is correlated disease recurrence and metastasis in advanced cancers such as breast, prostate and colorectal cancer. Genomic sequencing and proteomic analysis in a single CTC or bulk CTCs is expected to advance our understanding of tumor heterogeneity, mechanisms of disease metastasis, and mechanisms of intrinsic and acquired resistance to chemotherapy and immunotherapy . Ultimately, these analyses can be utilized to devise better therapeutic strategies. Hence, highly efficient isolation and acquisition of CTCs is critical for subsequent analysis of tumor specific genomic alterations and proteomic changes.

In the setting of either conventional treatment or novel therapies, patients will benefit from access to “real-time” highly-sensitive monitoring of disease burden. Our preliminary data7 has already demonstrated that such information can provide early insight into treatment efficacy and disease recurrence. While cross sectional imaging is an essential clinical tool, it cannot detect occult disease or treatment-induced changes in tumor genotypes. In our cancer center’s catchment area, lung cancer is the leading cause of cancer related deaths. We receive at least 50 new referrals per year from SCLC patients, which affords us the opportunity to study this disease in a prospective and longitudinal fashion. Overall, we will leverage our clinical acumen alongside our scientific expertise in studying mechanisms of sensitivity and resistance to therapeutic agents to develop innovative strategies to enhance the care of patients with SCLC.

 

References Cited
  1. Bernhardt, E.B. & Jalal, S.I. Small Cell Lung Cancer. Cancer Treat Res 170, 301-322 (2016).
  2. Gorin, M.A., et al. Circulating tumour cells as biomarkers of prostate, bladder, and kidney cancer. Nature reviews. Urology 14, 90-97 (2017).
  3. Hayes, D.F., et al. Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival. Clinical cancer research : an official journal of the American Association for Cancer Research 12, 4218-4224 (2006).
  4. Cohen, S.J., et al. Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26, 3213-3221 (2008).
  5. Cayrefourcq, L., et al. Establishment and characterization of a cell line from human circulating colon cancer cells. Cancer research 75, 892-901 (2015).
  6. Zhang, Z., et al. Expansion of CTCs from early stage lung cancer patients using a microfluidic co-culture model. Oncotarget 5, 12383-12397 (2014).
  7. Almodovar, K., et al. Longitudinal Cell-Free DNA Analysis in Patients with Small Cell Lung Cancer Reveals Dynamic Insights into Treatment Efficacy and Disease Relapse. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 13, 112-123 (2018).