2019 Translational Research Advances

Small Cell Lung Cancer Consortium

Molecular classification of small cell lung cancer.

Evidence from Small Cell Lung Cancer (SCLC) primary human tumors, patient-derived xenografts, cancer cell lines and genetically engineered mouse models indicate the convergence of a new model of SCLC subtypes defined by differential expression of four key transcription regulators: achaete-scute homologue 1 (ASCL1; also known as ASH1), neurogenic differentiation factor 1 (NeuroD1), yes-associated protein 1 (YAP1) and POU class 2 homeobox 3 (POU2F3). In this Perspectives article, the authors review and synthesize these recent findings to propose a working nomenclature for SCLC subtypes defined by relative expression of these four factors. Defining the unique therapeutic vulnerabilities of these subtypes of SCLC could help focus and accelerate therapeutic research, leading to rationally targeted approaches that may ultimately improve clinical outcomes for patients with this disease.

Citation:
Rudin CM, Poirier JT, Byers LA, Dive C, Dowlati A, George J, Heymach JV, Johnson JE, Lehman JM, MacPherson D, Massion PP, Minna JD, Oliver TG, Quaranta V, Sage J, Thomas RK, Vakoc CR, Gazdar AF. Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. Nat Rev Cancer. 2019 May;19(5):289-297. doi: 10.1038/s41568-019-0133-9. Review. Erratum in: Nat Rev Cancer. 2019 Jun 7; PMID: 30926931

NCI Workshop on Lineage Plasticity and Androgen Receptor-Independent Prostate Cancer

The role of lineage plasticity in prostate cancer therapy resistance.

NCI-funded investigators with expertise in prostate cancer and neuroendocrine tumors, including the prostate SPOREs, met with NCI intramural and extramural staff in December 2018 to participate in a workshop to understand the emergence of a treatment-associated small cell, neuroendocrine (t-SCNC) population of prostate cancer cells.

During prolonged androgen deprivation therapies (ADT), tumor cells in 20% of patients become resistant to the treatment and begin to grow as small cell endocrine tumors, a demonstration of plasticity from their luminal cell lineage. This publication provides summaries and analyses of the working groups that defined knowledge gaps and suggested approaches to address: i) how lineage plasticity occurs (ii) the timing and cooperation of lineage-derived transcription factors and of emerging drivers (iii) what preclinical models can recapitulate the biology of disease and the recognized phenotypes and (iv) identification of therapeutic targets and novel trial designs. The discussion includes mechanisms underlying this process and provides a path towards developing biomarkers and trials to support this molecularly unique set of patients.

Citation:
Beltran H, Hruszkewycz A, Scher HI, Hildesheim J, Isaacs J, Yu EY, Kelly K, Lin D, Dicker A, Arnold J, Hecht T, Wicha M, Sears R, Rowley D, White R, Gulley JL, Lee J, Diaz Meco M, Small EJ, Shen M, Knudsen K, Goodrich DW, Lotan T, Zoubeidi A, Sawyers CL, Rudin CM, Loda M, Thompson T, Rubin MA, Tawab-Amiri A, Dahut W, Nelson PS. Clin Cancer Res. 2019 Jul 30. doi: 10.1158/1078-0432.CCR-19-1423. PMID: 31363002