Photo of Daniel P. Silver,  MD, PhD

Daniel P. Silver, MD, PhD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute

Daniel P. Silver, MD, PhD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

  • Assistant Professor, Medicine, Harvard Medical School
  • Assistant Professor of Medicine, Medical Oncology/Cancer Biology, Dana-Farber Cancer Institute

DF/HCC PROGRAM AFFILIATION

Research Abstract

As a physician scientist, the work of my laboratory focuses on basic and translational science aimed ultimately at improving the care of cancer patients. My research centers on two areas, first, discovering new oncogenes that may be targets for cancer therapy, and second, the functions of the BRCA1 and BRCA2 genes, genomic instability, and the relationship between DNA repair lesions and therapy, particularly for triple-negative breast cancer.

We have devised a series of new genome-wide screens to identify novel oncogenic activities that may represent targets for cancer therapy. This screen has identified a number of genes that can play the role of activated RAS in cancer. Some of these genes appear to be amplified and overexpressed in human cancers; we are currently investigating their significance in human malignancy. We are optimistic that some of these new candidate oncogenes may suggest new therapeutic strategies.

Women who have one mutated copy of either the BRCA1 or the BRCA2 gene have very high rates of breast and ovarian cancer. Understanding the functions of these two genes is vital to devise targeted therapies to treat the cancers that arise in these individuals. We have previously shown BRCA1 or BRCA2 loss rapidly results in genomic instability characterized by gross chromosomal rearrangements. In addition, a subset of sporadic breast cancers, the basal-like tumors, bears great similarity to BRCA1-deficient breast cancers, leading to the hypothesis that these tumors share with BRCA1-deficient tumors a defect in genomic integrity maintenance. We are deeply involved in the DF/HCC effort to investigate cisplatin as a treatment of triple-negative breast cancer, a natural outgrowth of our interests in DNA repair defects caused by BRCA1 pathway failure. We helped analyze the DF/HCC clinical trial showing the clinical utility of platinum chemotherapy for sporadic triple-negative breast cancer, and then had a pivotal role in creating a new predictive biomarker of cisplatin response, a biomarker that is now the subject of an ongoing prospective clinical trial. We are also involved in the Dana-Farber/Harvard Cancer Center SPORE in breast cancer in several capacities as well.

 

Publications

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  • Silver DP, Livingston DM. Mechanisms of BRCA1 tumor suppression. 2012; 2:679-84. PubMed
  • Birkbak NJ, Wang ZC, Kim JY, Eklund AC, Li Q, Tian R, Bowman-Colin C, Li Y, Greene-Colozzi A, Iglehart JD, Tung N, Ryan PD, Garber JE, Silver DP, Szallasi Z, Richardson AL. Telomeric Allelic Imbalance Indicates Defective DNA Repair and Sensitivity to DNA-Damaging Agents. 2012; 2:366-75. PubMed
  • Tung N, Silver DP. Chek2 DNA damage response pathway and inherited breast cancer risk. J Clin Oncol 2011; 29:3813-5. PubMed
  • Tung N, Miron A, Schnitt SJ, Gautam S, Fetten K, Kaplan J, Yassin Y, Buraimoh A, Kim JY, Szasz AM, Tian R, Wang ZC, Collins LC, Brock J, Krag K, Legare RD, Sgroi D, Ryan PD, Silver D, Garber JE, Richardson AL. Prevalence and predictors of loss of wild type BRCA1 in estrogen receptor positive and negative BRCA1-associated breast cancers. Breast Cancer Res 2010; 12:R95. PubMed
  • Liu JF, Silver DP. Poly ADP-ribose polymerase inhibitors: science and current clinical development. Curr Opin Oncol 2010; 22:567-72. PubMed
  • Anders CK, Winer EP, Ford JM, Dent R, Silver DP, Sledge GW, Carey LA. Poly(ADP-Ribose) polymerase inhibition: "Targeted" therapy for triple-negative breast cancer. Clin Cancer Res 2010; 16:4702-10. PubMed
  • Silver DP, Richardson AL, Eklund AC, Wang ZC, Szallasi Z, Li Q, Juul N, Leong CO, Calogrias D, Buraimoh A, Fatima A, Gelman RS, Ryan PD, Tung NM, De Nicolo A, Ganesan S, Miron A, Colin C, Sgroi DC, Ellisen LW, Winer EP, Garber JE. Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. J Clin Oncol 2010; 28:1145-53. PubMed
  • Stephens PJ, McBride DJ, Lin ML, Varela I, Pleasance ED, Simpson JT, Stebbings LA, Leroy C, Edkins S, Mudie LJ, Greenman CD, Jia M, Latimer C, Teague JW, Lau KW, Burton J, Quail MA, Swerdlow H, Churcher C, Natrajan R, Sieuwerts AM, Martens JW, Silver DP, Langerød A, Russnes HE, Foekens JA, Reis-Filho JS, van 't Veer L, Richardson AL, Børresen-Dale AL, Campbell PJ, Futreal PA, Stratton MR. Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 2009; 462:1005-10. PubMed
  • Zhao JJ, Silver DP. Estrogen Receptor-Negative Breast Cancer: New Insights into Subclassification and Targeting. Clin Cancer Res 2009; 15:6309-10. PubMed
  • Kalaszczynska I, Geng Y, Iino T, Mizuno S, Choi Y, Kondratiuk I, Silver DP, Wolgemuth DJ, Akashi K, Sicinski P. Cyclin A is redundant in fibroblasts but essential in hematopoietic and embryonic stem cells. Cell 2009; 138:352-65. PubMed
  • Iglehart JD, Silver DP. Synthetic lethality--a new direction in cancer-drug development. N Engl J Med 2009; 361:189-91. PubMed
  • Matera I, Watkins-Chow DE, Loftus SK, Hou L, Incao A, Silver DL, Rivas C, Elliott EC, Baxter LL, Pavan WJ. A sensitized mutagenesis screen identifies Gli3 as a modifier of Sox10 neurocristopathy. Hum Mol Genet 2008; 17:2118-31. PubMed
  • Zhu W, Saddar S, Seetharam D, Chambliss KL, Longoria C, Silver DL, Yuhanna IS, Shaul PW, Mineo C. The scavenger receptor class B type I adaptor protein PDZK1 maintains endothelial monolayer integrity. Circ Res 2008; 102:480-7. PubMed
  • Livingston DM, Silver DP. Cancer: crossing over to drug resistance. Nature 2008; 451:1066-7. PubMed
  • Silver DL, Hou L, Somerville R, Young ME, Apte SS, Pavan WJ. The secreted metalloprotease ADAMTS20 is required for melanoblast survival. PLoS Genet 2008; 4:e1000003. PubMed
  • Gopal M, Silver D. Fibromatosis of the appendix and cecum. J Minim Invasive Gynecol 2007; 14:678. PubMed
  • Silver DP, Dimitrov SD, Feunteun J, Gelman R, Drapkin R, Lu SD, Shestakova E, Velmurugan S, Denunzio N, Dragomir S, Mar J, Liu X, Rottenberg S, Jonkers J, Ganesan S, Livingston DM. Further evidence for BRCA1 communication with the inactive X chromosome. Cell 2007; 128:991-1002. PubMed
  • Ganesan S, Richardson AL, Wang ZC, Iglehart JD, Miron A, Feunteun J, Silver D, Livingston DM. Abnormalities of the Inactive X Chromosome Are a Common Feature of BRCA1 Mutant and Sporadic Basal-like Breast Cancer. Cold Spring Harb Symp Quant Biol 2006; 70:93-7. PubMed
  • Tuveson DA, Shaw AT, Willis NA, Silver DP, Jackson EL, Chang S, Mercer KL, Grochow R, Hock H, Crowley D, Hingorani SR, Zaks T, King C, Jacobetz MA, Wang L, Bronson RT, Orkin SH, DePinho RA, Jacks T. Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 2004; 5:375-87. PubMed
  • Ganesan S, Silver DP, Drapkin R, Greenberg R, Feunteun J, Livingston DM. Association of BRCA1 with the inactive X chromosome and XIST RNA. Philos Trans R Soc Lond B Biol Sci 2004; 359:123-8. PubMed
  • Silver DP. HIN-1 and the nosology of breast cancer. Cancer Biol Ther 2003; 2:564-5. PubMed
  • Ganesan S, Silver DP, Greenberg RA, Avni D, Drapkin R, Miron A, Mok SC, Randrianarison V, Brodie S, Salstrom J, Rasmussen TP, Klimke A, Marrese C, Marahrens Y, Deng CX, Feunteun J, Livingston DM. BRCA1 supports XIST RNA concentration on the inactive X chromosome. Cell 2002; 111:393-405. PubMed
  • Sharpless NE, Alson S, Chan S, Silver DP, Castrillon DH, DePinho RA. p16(INK4a) and p53 deficiency cooperate in tumorigenesis. Cancer Res 2002; 62:2761-5. PubMed
  • Silver DP, Livingston DM. Self-excising retroviral vectors encoding the Cre recombinase overcome Cre-mediated cellular toxicity. Mol Cell 2001; 8:233-43. PubMed
  • Iglehart JD, and Silver DP. A New Direction in Cancer-Drug Development NEJM 2009.
  • Chen J, Silver DP, Walpita D, Cantor SB, Gazdar AF, Tomlinson G, Couch FJ, Weber BL, Ashley T, Livingston DM, Scully R. Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells. Mol Cell 1998; 2:317-28. PubMed
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