Perspective: Opportunities in recalcitrant, rare and neglected tumors

Abstract

The ‘Recalcitrant Cancer Research Act of 2012’ defines recalcitrant cancers as having a 5-year survival rate of <20% and estimated to cause the death of at least 30,000 individuals in the US each year. Cancers specifically mentioned in the act are lung and pancreatic cancers. In addition to recalcitrant tumors, rare tumors are often neglected in the drug discovery arena. Sarcomas are ~1% of cancers. The NCI Specialized Programs of Research Excellence (SPOREs) provide disease-focused cancer center grants specifically to accelerate the impact of laboratory research on the treatment of patients. There are 3 SPOREs focused on pancreatic cancer, 7 SPOREs focused on lung cancer and 1 SPORE focused on sarcoma. Through the Developmental Therapeutics Program (DTP), NCI maintains the infrastructure and expertise for the operation of cell-free and cell-based high-, medium- and low-throughput assays. The current effort is on sarcoma, SCLC and pancreatic lines. The DTP functional genomics laboratory provides molecular analyses including gene expression microarrays, exon arrays, microRNA arrays, multiplexing gene assays, plus others as tools to identify potential drug targets and to determine the role of selected genes in the mechanism(s) of drug action and cellular responses to stressors. The DTP tumor microenvironment laboratory focuses on the discovery of targets and the development of therapeutic strategies targeting the tumor microenvironment and physiological abnormalities of tumors resulting from environmental factors or alterations in metabolic enzymes. The DTP maintains a group focused on determining the mechanism(s) of action and identifying potential surrogate markers of activity for select compounds integrating proteomics, transcriptomics and molecular biology platforms. In conclusion, the NCI has active SPORE programs and an internal effort focused on recalcitrant, rare and neglected cancers which are generating data toward improving treatment of these difficult diseases.

Small Cell Lung Cancer: Will Recent Progress Lead to Improved Outcomes?

“…Results from this drug screen, as well as others, coupled with intense analyses of the pathways affected by the indicated agents utilizing the comprehensive methods indicated above may provide indications for future clinical trials (50). …”

Small cell lung cancer: Where do we go from here?

“…Toward this goal, a major initiative to characterize drug sensitivity is ongoing at the NCI through the Developmental Therapeutics Program, which is investigating more than 400 targeted drugs and 100 FDA‐approved oncology therapies in a panel of >60 SCLC cell lines. Results from this drug screen and other ongoing preclinical efforts—combined with an integrated analysis of the molecular profiles of these SCLC cell lines (eg, mutations, amplifications, deletions, or alterations at the protein or pathway levels that correspond to drug sensitivity)—will provide important leads that can be validated in the laboratory and taken forward into clinical trials. As part of this, bioinformatics tools will allow us to mine these growing data sets for the new targets or biomarkers to maximize the value and use of a growing molecular resource/database in SCLC …”

Perspectives in small cell lung cancer

“…Toward this goal, a major initiative to characterize drug sensitivity is ongoing at the NCI through the Developmental Therapeutics Program, which is investigating more than 400 targeted drugs and 100 FDA-approved oncology therapies in a panel of >60 SCLC cell lines. Results from this drug screen and other ongoing preclinical efforts-combined with an integrated analysis of the molecular profiles of these SCLC cell lines (e. g., mutations, amplifications, deletions, or alterations at the protein or pathway levels that correspond to drug sensitivity) -will provide important leads that can be validated in the laboratory and taken forward into clinical trials (60). Another problem is the paucity of data regarding whole-exome DNA sequencing in SCLC.…”