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U.S. National Institutes of Health
Last Updated: 03/17/14

Molecular Pharmacology Branch (MPB)

MPB’s mission is to improve the treatment of recalcitrant, rare and neglected cancers through the discovery of potential therapeutic targets, the screening of new agents, the identification of genomic vulnerabilities, and the identification of potential therapeutic combinations using state-of-the-art drug discovery, molecular characterization, and mechanism-of-action techniques and through interactions collaboration with the cancer research community and other NCI laboratories. To achieve these goals, the MPB operates four laboratories at the Frederick National Laboratories for Cancer Research: the classic NCI60 cell line screen, the Target Validation and Screening Laboratory, the Functional Genomics Laboratory, and the Translational Support Laboratory. MPB is currently focused on sarcoma and small cell lung cancer, and as a starting place, has collections of 70-80 human sarcoma cell lines and 70-80 human small cell lung cancer cell lines.

Sarcoma are about 1% of cancers. Within that 1% are widely varied tumors. Sarcoma occur in patients of all ages with frequency spread evenly over the human age range. Sarcoma are tumors of mesenchymal origin. The mesenchymal stem cell, a pluripotent cell, which gives rise to varied differentiated cells including osteocytes, adipocytes, chondrocytes, muscle cells, fibroblasts, neural cells and stromal cells, is the most likely ultimate cell of origin for sarcoma. When mesenchymal stem cell genetics go wrong and malignant transformation occurs sarcoma including osteosarcoma, Ewing’s sarcoma, chondrosarcoma, rhabdomyo-sarcoma, synovial sarcoma fibrosarcoma, liposarcoma and many others can initiate. Our knowledge of sarcoma genetics is increasing rapidly. Two general groups are sarcoma arising from chromosomal translocations and sarcoma with very complex genetics. Genes that are frequently mutated in sarcoma include TP53, NF1, PIK3CA, HDAC1, IDH1 and 2, KDR, KIT and MED12. Genes that are frequently amplified in sarcoma include CDK4, YEATS4, HMGA2, MDM2, JUN, DNM3, FLT4, MYCN, MAP3K5, GLI1 and the microRNAs miR-214 and miR-199a2. Genes that are up-regulated in sarcoma include MUC4, CD24, FOXL1, ANGPTL2, HIF1a, MDK, cMET, TIMP-2, PRL, PCSK1, IGFR-1, TIE1, KDR, TEK, FLT1 and several microRNAs. While some alterations occur in specific subtypes of sarcoma, others cross several sarcoma types.1 Discovering and developing new therapeutic approaches for these relentless diseases is critical. The detailed knowledge of sarcoma genetics may allow development of sarcoma subtype-targeted therapeutics.

Small cell lung cancer (SCLC) is an extremely aggressive, recalcitrant cancer that frequently recurs after chemotherapy. SCLC is a neuroendocrine subtype of lung cancer that affects >200,000 people world-wide every year with a very high mortality rate. In the US, SCLC represents 13-15% of lung cancer cases and is the most aggressive form of lung cancer with nearly as many deaths as diagnoses per year. In 2011 >25,000 deaths were attributable to this disease in the US alone.2 Although initially a chemotherapy and radiation-sensitive disease, only 5% of patients survive five years and the median survival of SCLC patients is <1 year. Over the past 3 decades there have been >52 SCLC phase 3 clinical trials testing varied cytotoxic therapieswith few improvements in SCLC treatment.3 The combination of etoposide and cisplatin remains standard first-line therapy for SCLC. In 2003 topotecan became the only drug approved for treatment of patients with relapsed SCLC. From 1977 through 1992, 126 SCLC cell lines were established from NCI-Navy Medical Oncology Branch patients. MYC family DNA amplification was present in 36% of SCLC lines from previously treated patients compared to 11% of lines from untreated patients. MYC DNA amplification in SCLC lines established from previously treated patients was associated with shorter survival.4, 5 The apoptosis-related gene caspase 8 is frequently silenced in SCLC tumors and cell lines usuallyby aberrant promoter methylation. In SCLC lines the caspase 8 gene expression was frequently lost (79%). MYC amplification is present in 45% of SCLC lines which had lost caspase 8 expression, but not in caspase 8 positive lines. There was also a high rate of loss of CASP10, DR5, FAS and FASL in SCLC. The loss of expression of proapoptotic components was higher in MYC-amplified SCLC lines.6 A SCLC subset is dependent on activation of hedgehog signaling, an embryonic pathway implicated in development, morphogenesis and the regulation of stem cell fates.7, 8 SCLC has a unique biology with characteristic chromosomal changes; dysregulation of tumor suppressor genes, oncogenes, and signaling pathways; and active early development pathways.9

New therapeutic approaches are needed to improve long-term survival in these diseases. The challenge of sarcoma is 50-100 unique diseases, each with relatively small patient populations. Preclinically, growing many types of sarcoma as xenografts has been difficult making in vivo proof of activity of agents in some types of sarcoma difficult. With SCLC the challenge is working with the cells in culture. SCLC grows as clusters making it difficult to get accurate cell counts at the beginning and conclusion of experiments. In clinical trial, the extreme aggressiveness of recurrent SCLC is a challenge in assessing the efficacy of new therapies. MPB has taken on these diseases and will provide a public database on the cell line panels including: 1) gene/exon expression, 2) microRNA expression, 3) mutations, 4) subpopulations, 5) response to standard and investigational anticancer agents, 6) protein expression & activated pathways and 7) cell surface and intracellular markers. These data are offered as a resource to the cancer research community. The panels and the characterization data will be used to identify targets and target combinations from which to generate new drug discovery endeavors agnostic with respect to therapeutic approach in the cancer research community. Currently, the sarcoma and SCLC lines are being screened in 9-point concentration response in triplicate to all FDA approved anticancer agents and about 400 investigational agents, characterized genetically by exon array and microRNA array, characterized for cell surface protein expression, and assessed for metabolic alterations.

REFERENCES

  1. Teicher BA. Searching for molecular targets in sarcoma. Biochem Pharmacol 2012;84:1-10.

  2. Siegel R, Naishadham D, Jemal A. Cancer statistics. CA Cancer J Clin 2012;62:10-29.

  3. Oze I, Hotta K, Kiura K, Ochi N, Takigawa N, Fujiwara Y, et al. Twenty-seven years of phaseIII trials for patients with extensive disease small-cell lung cancer: disappointing results. PlosOne 2009;4:e7835.

  4. Johnson BE, Ihde DC, Makuch RW, Gazdar AF, Carney DN, Loe H, Russell E, Nau MN, Minna JD. Myc family oncogene amplification in tumor cell lines established from small cell lung cancer patients and its relationship to clinical status and course . J Clin Invest 1987; 79: 1629-34.

  5. Johnson BE, Russell E, Simmons AM, Phelps R, Steinberg SM, Ihde DC, Gazdar AF. MYC family DNA amplification in 126 tumor cell lines from patients with small cell lung cancer. J Cell Biochem Suppl 24 1996; 24: 210-17.

  6. Shivapurkar N, Reddy J, Matta H, Sathyanarayana UG, Huang CX, Toyooka S, Minna JD, Chaudhary PM, Gazdar AF. Loss expression of death-inducing signaling complex (DISC) compoents in lung cancer cell lines and the influence of MYC amplification. Oncogene 2002; 21: 8510-4.

  7. Park K-S, Martelotto LG, Peifer M, Sos ML, Karnezis AN, Mahjoub MR, Bernard K, Conklin JF, Szczepny A, Yuan J, Guo R, Ospina Β, Falzon J, Bennett S, Brown TJ, Markovic A, Devereux WL, Ocasio CA, Chen JK, Stearns T, Thomas RK, Dorsch M, Buonamici S, Watkins DN, Peacock CD, Sage J. A critical requirement for hedgehog signaling in small cell lung cancer. Nature Med 2011; 17: 1504-??

  8. Watkins DN, Berman DM, Baylin SB. Hedgehog signaling: progenitor phenotype in small cell lung cancer. Cell Cycle 2003; 2: 196-8.

  9. D’Angelo SP, Pietanza MC. The molecular pathogenesis of small cell lung cancer. Cancer Biol Ther 2010; 10: 1-10.