OMB No. 0925-0001 and 0925-0002 (Rev. 10/2021 Approved Through 09/30/2024)

BIOGRAPHICAL SKETCH

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1. Personal Statement
   The focus of my laboratory is the identification and biologic characterization of genetic alterations that promote cancer development and predict drug response. Representative work includes a 2006 paper demonstrating that tumors with BRAF mutation are selectively sensitive to MEK inhibition (Solit et al., Nature, 2006). My laboratory was also the first to demonstrate that RAF splice variants are a common mechanism of resistance to selective RAF inhibitors such as vemurafenib (Poulikakos et al., Nature, 2011). Since 2001, I have been a practicing Genitourinary Medical Oncologist and was formerly the MSK Director of Early Drug Development. I have also served as the Director of the MSK Center for Molecular Oncology (CMO) since its founding in 2014. The CMO mission is to facilitate the prospective and retrospective molecular characterization of patient tumors (and now also tumor derived plasma DNA) with the goals of guiding standard care, accelerating enrollment into therapeutic clinical trials, identifying alterations that increase heritable cancer risk and identifying novel markers of drug sensitivity and resistance. Over the past decade, my laboratory has focused on the defining the genetic basis for bladder cancer pathogenesis and the influence of morphologic and tumor heterogeneity on clinical outcomes and response to local and systemic therapies. For the P01, I will serve as the PI of Project 1.

1. Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, Shi H, Atefi M, Titz B, Gabay MT, Salton M, Dahlman KB, Tadi M, Wargo JA, Flaherty KT, Kelley MC, Misteli T, Chapman PB, Sosman JA, Graeber TG, Ribas A, Lo RS, Rosen N, Solit DB. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature. 2011; 480:387–390. PMCID: PMC3266695.
2. Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, Pirun M, Sander C, Socci ND, Ostrovnaya I, Viale A, Heguy A, Peng L, Chan TA, Bochner B, Bajorin DF, Berger MF, Taylor BS, Solit DB. Genome sequencing identifies a basis for everolimus sensitivity. Science. 2012; 338:221. PMCID: PMC3633467.
3. Hyman DM, …, Arteaga CL, Meric-Bernstam F, Baselga J, Solit DB. HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature. 2018; 554(7691):189-194; Epub 2018 Feb 8. Jan 31. PMID: 29420467. PMCID: PMC5808581.

Ongoing and recently completed projects that I would like to highlight include:

1 P50 CACA221745-03 (PI: Solit/Bajorin)                                          8/24/2018–7/31/2024

NIH/NCI

SPORE in Bladder Cancer

Project 1 will seek to use molecular profiling to identify those patients most amenable to a curative-intent bladder sparing approach.

Role: SPORE Principal Investigator (w/ D Bajorin), Program Director - Developmental Research Program,

Basic Science Lead RP-1 - Defining Predictors of Sensitivity to Cisplatin-Based Chemotherapy in Urothelial Cancer (w/ Dr. Gopa Iyer)

1 P01-CA221757-03 (PI: Abate-Shen)                                          9/11/2018–8/31/2024

NIH/NCI

Modeling bladder cancer pathogenesis and tumor evolution

Project 1: Role of the H3K27 demethylase KDM6A in bladder cancer pathogenesis will use human tumors. This project will use patient derived and engineered cell line, organoid and mouse models to elucidate the role of KDM6A mutations in promoting bladder cancer initiation and progression.

Role: Principal Investigator, Project 1

1 R01 CA233899-02 (PI: Al-Ahmadie)                             2/1/2019 - 1/31/2024             

NCI             

Defining the impact of intra-tumoral morphologic, immune and mutational heterogeneity in urothelial carcinoma

The goal of this project is to determine whether regions of morphologic heterogeneity within the primary tumor are the source of metastatic and resistant disease following immune checkpoint inhibitors therapy.

Role: Co-Investigator

B.              Positions, Scientific Appointments, and Honors
Positions and Employment

2022–              Chief, Molecular Medicine Service, Human Oncology and Pathogenesis Program (HOPP), MSK, New York, NY

2015–               Attending Physician, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSK), New York, NY

2015–              Member and Laboratory Head, HOPP, MSK, New York, NY

2015–              Professor (Medicine, Cell and Developmental Biology), Weill Cornell Medical School and Graduate School of Medical Studies, NY, NY

2013–              Director, MSK Kravis Center for Molecular Oncology, New York, NY

2013–              Geoffrey Beene Chair, MSK, New York, NY

2012–2015              Associate Professor, Weill Cornell Medical Center, New York, NY

2011–2014              Associate Attending Physician, Department of Medicine, MSK, New York, NY

2011–2014              Associate Member and Laboratory Head, HOPP, MSK, New York, NY

2006–2011              Assistant Professor of Medicine, Weill Cornell Medical Center, New York, NY

2006–2011              Assistant Member and Laboratory Head, Human Oncology and Pathogenesis Program (HOPP), MSK, New York, NY

2005–2011              Assistant Attending Physician (Level 2), Department of Medicine, MSK, New York, NY

2001–2006              Instructor in Medicine, Weill Cornell Medical Center, New York, NY

2001–2005              Assistant Attending Physician (Level 1), Department of Medicine, MSK, New York, NY

Other Experience and Professional Memberships

2021–              Chairperson, NIH Developmental Therapeutics Study Section

2019–              Member, Association of American Physicians

2016              Cancer Moonshot, Blue Ribbon Panel, Tumor Evolution and Progression Working Group

2013–              Grant Review Committee, Melanoma Research Alliance (Chair 2012–2015)

2014–              Scientific Editorial Board, Cancer Discovery

2011–              Member, American Society for Clinical Investigation

2012–              Senior Editor, Cancer Research

2011–              Editorial Board, Molecular Cancer Therapeutics

2010–              Editorial Board, Clinical Cancer Research

1999–              Member, American Association for Cancer Research

1999–              Member, American Society of Clinical Oncology (ASCO)

Honors

2019–              Inducted, Association of American Physicians

2013–              Incumbent, Geoffrey Beene Chair in Cancer Research

2011              Inducted, American Society of Clinical Investigation

2007–2011              Incumbent, Elizabeth and Felix Rohatyn Chair for Junior Faculty

2007              Boyer Award for Excellence in Clinical Research

2007              Kimmel Scholars Award

2002              ASCO Career Development Award

2001              ASCO Young Investigator Award

2001              Doris Duke Translational Research Award

2000              NIH Clinical Scholars Research Fellow

1992              Phi Beta Kappa, University of Pennsylvania

1991              Summa Cum Laude, University of Pennsylvania

C.              Contributions to Science

1. My laboratory has been a leader in the use of next-generation sequencing methods to identify biomarkers of drug sensitivity and resistance. A long-standing problem in oncology is the variability of treatment response observed in early-stage clinical trials. Our group pioneered the use of whole-genome sequencing methods to identify occult predictors of drug response. In an early example, we identified mutations in TSC1 and NF2 as the molecular basis for extreme sensitivity of a patient with metastatic bladder cancer to the mTORC1 inhibitor everolimus. This work was the inspiration for the NCI’s Exceptional Responder (N-of-1) initiative, which studies outlier clinical responders to both cytotoxic and targeted cancer agents in detail, in order to identify novel biomarkers of response and resistance.
1. Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, Pirun M, Sander C, Socci ND, Ostrovnaya I, Viale A, Heguy A, Peng L, Chan TA, Bochner B, Bajorin DF, Berger MF, Taylor BS†, Solit DB†. Genome sequencing identifies a basis for everolimus sensitivity. Science. 2012;338:221. PMCID: PMC3633467. †Co-corresponding authors.
2. Al-Ahmadie H, Iyer G, Hohl M, Asthana S, Inagaki A, Schultz N, Hanrahan AJ, Scott SN, Brannon AR, McDermott GC, Pirun M, Ostrovnaya I, Kim P, Socci ND, Viale A, Schwartz GK, Reuter V, Bochner BH, Rosenberg JE, Bajorin DF, Berger MF, Petrini JH†, Solit DB†, Taylor BS†. Synthetic lethality in ATM-deficient RAD50-mutant tumors underlies outlier response to cancer therapy. Cancer Discovery. 2014;4:1014–1021. PMCID: PMC4155059. †Co-corresponding authors.
3. Van Allen EM, Mouw KW, Kim P, Iyer G, Wagle N, Al-Ahmadie H, Zhu C, Ostrovnaya I, Kryukov GV, O'Connor KW, Sfakianos J, Garcia-Grossman I, Kim J, Guancial EA, Bambury R, Bahl S, Gupta N, Farlow D, Qu A, Signoretti S, Barletta JA, Reuter V, Boehm J, Lawrence M, Getz G, Kantoff P, Bochner BH, Choueiri TK, Bajorin DF, Solit DB, Gabriel S, D'Andrea A, Garraway LA, Rosenberg JE. Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma. Cancer Discovery. 2014;4:1140–1153. PMCID: PMC4238969.
4. Grisham RN, Sylvester BE, Won H, McDermott G, DeLair D, Ramirez R, Yao Z, Shen R, Dao F, Bogomolniy F, Makker V, Sala E, Soumerai TE, Hyman DM, Socci ND, Viale A, Gershenson DM, Farley J, Levine DA, Rosen N, Berger MF, Spriggs DR, Aghajanian CA, Solit DB, Iyer G. Extreme outlier analysis identifies occult mitogen-activated protein kinase pathway mutations in patients with low-grade serous ovarian cancer. J Clin Oncol. 2015;33:4099–4105. PMCID: PMC4669594.
2. My laboratory has a longstanding interest in defining the genomic landscape of bladder cancer, with a focus on determining the influence of morphologic and genomic heterogeneity or clinical outcomes and treatment response. As part of these studies we have sought to develop novel patient derived organoid and xenograft models that can be used to study the biologic role of mutant oncoproteins and there influence on treatment response. The long-term goal is to use this knowledge to identify novel therapeutic targets and predictive biomarkers.
1. Iyer G, Al-Ahmadie H, Schultz N, Hanrahan AJ, Ostrovnaya I, Balar AV, Kim PH, Lin O, Weinhold N, Sander C, Zabor EC, Janakiraman M, Garcia-Grossman IR, Heguy A, Viale A, Bochner BH, Reuter VE, Bajorin DF, Milowsky MI, Taylor BS, Solit DB. Prevalence and co-occurrence of actionable genomic alterations in high-grade bladder cancer. J Clin Oncol. 2013;31:3133–3140. PMCID: PMC3753703.
2. Al-Ahmadie HA, Iyer G, Lee BH, Scott SN, Mehra R, Bagrodia A, Jordan EJ, Gao SP, Ramirez R, Cha EK, Desai NB, Zabor EC, Ostrovnaya I, Gopalan A, Chen YB, Fine SW, Tickoo SK, Gandhi A, Hreiki J, Viale A, Arcila ME, Dalbagni G, Rosenberg JE, Bochner BH, Bajorin DF, Berger MF, Reuter VE, Taylor BS, Solit DB. Frequent somatic CDH1 loss-of-function mutations in plasmacytoid variant bladder cancer. Nat Genetics. 2016;48:356–358. PMCID: PMC4827439.
3. Lee SH, Hu W, Matulay JT, Silva MV, Owczarek TB, Kim K, Chua CW, Barlow LJ, Kandoth C, Williams AB, Bergren SK, Pietzak EJ, Anderson CB, Benson MC, Coleman JA, Taylor BS, Abate-Shen C, McKiernan JM, Al-Ahmadie H, Solit DB, Shen MM. Tumor Evolution and Drug Response in Patient-Derived Organoid Models of Bladder Cancer. Cell. 2018 Apr 5. PMID: 29625057. PMCID: PMC5890941.
4. Kim K, Hu W, Audenet F, Almassi N, Hanrahan AJ, Murray K, Bagrodia A, Wong N, Clinton TN, Dason S, Mohan V, Jebiwott S, Nagar K, Gao J, Penson A, Hughes C, Gordon B, Chen Z, Dong Y, Watson PA, Alvim R, Elzein A, Gao SP, Cocco E, Santin AD, Ostrovnaya I, Hsieh JJ, Sagi I, Pietzak EJ, Hakimi AA, Rosenberg JE, Iyer G, Vargas HA, Scaltriti M, Al-Ahmadie H, Solit DB†, Coleman JA†. Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts. Nature Communications. 2020 Apr 24. PMID: 32332851. PMCID: PMC7181640. †Co-corresponding authors.
3. As the inaugural Directors of the MSK Center for Molecular Oncology, I collaborate extensively with clinical, translational and laboratory investigators to assess the utility of molecular profiling with the goal of identifying subsets of patients most likely to respond to targeted pathway inhibitors and immunotherapy and germline mutations associated with increased heritable cancer risk. Our studies also seek to identify mechanisms of drug resistance as a basis for the development of rational combination strategies. 
1. Zehir A, Benayed R, Shah RH, Syed A, Middha S, Kim HR, Srinivasan P, Gao J, Chakravarty D, Devlin SM, Hellmann MD, ….., Solit DB, Ladanyi M, Berger MF. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017 May 8. [Epub ahead of print.] Jun;23(6):703-713. PMCID: PMC5461196.
2. Mandelker D, Zhang L, Kemel Y, Stadler ZK, Joseph V, Zehir A, …., Scher HI, Baselga J, Klimstra DS, Solit DB, Hyman DM, Berger MF, Ladanyi M, Robson ME, Offit K. Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. JAMA. 2017 Sep 5. PMCID: PMC5611881.
3. Hyman DM, Piha-Paul SA, Won H, Rodon J, Saura C, Shapiro GI, Juric D, Quinn DI, Moreno V, Doger B, Mayer IA, Boni V, Calvo E, Loi S, Lockhart AC, Erinjeri JP, Scaltriti M, Ulaner GA, Patel J, Tang J, Beer H, Selcuklu SD, Hanrahan AJ, Bouvier N, Melcer M, Murali R, Schram AM, Smyth LM, Jhaveri K, Li BT, Drilon A, Harding JJ, Iyer G, Taylor BS, Berger MF, Cutler RE Jr, Xu F, Butturini A, Eli LD, Mann G, Farrell C, Lalani AS, Bryce RP, Arteaga CL, Meric-Bernstam F, Baselga J, Solit DB. Author Correction: HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature. 2019 Feb. PMID: 30755741.
4. Nguyen B, Fong C, Luthra A, Smith SA, DiNatale RG, Nandakumar S, Walch H, Chatila WK, Madupuri R, Kundra R, Bielski CM, Mastrogiacomo B, Donoghue MTA, Boire A, Chandarlapaty S, Ganesh K, Harding JJ, Iacobuzio-Donahue CA, Razavi P, Reznik E, Rudin CM, Zamarin D, Abida W, Abou-Alfa GK, Aghajanian C, Cercek A, Chi P, Feldman D, Ho AL, Iyer G, Janjigian YY, Morris M, Motzer RJ, O'Reilly EM, Postow MA, Raj NP, Riely GJ, Robson ME, Rosenberg JE, Safonov A, Shoushtari AN, Tap W, Teo MY, Varghese AM, Voss M, Yaeger R, Zauderer MG, Abu-Rustum N, Garcia-Aguilar J, Bochner B, Hakimi A, Jarnagin WR, Jones DR, Molena D, Morris L, Rios-Doria E, Russo P, Singer S, Strong VE, Chakravarty D, Ellenson LH, Gopalan A, Reis-Filho JS, Weigelt B, Ladanyi M, Gonen M, Shah SP, Massague J, Gao J, Zehir A, Berger MF, Solit DB, Bakhoum SF, Sanchez-Vega F, Schultz N. Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients. Cell. 2022 Feb 3. PMID: 35120664. PMCID: PMC9147702.

4. A major focus of early research was the development of selective inhibitors of RAF and MEK as a therapeutic strategy for the treatment of cancers with mutational activation of the MAP kinase pathway. In our initial studies, we demonstrated that tumors with mutant BRAF were selectively dependent upon MAP kinase activity for cell cycle progression and survival. These data suggested that MEK inhibitors may have clinical utility in patients whose tumors harbor mutant BRAF, a hypothesis that has now been clinically validated with the FDA approval of the MEK inhibitor trametinib for the treatment of patients with BRAF mutant melanoma.

1. Solit DB, Garraway LA, Pratilas CA, Sawai A, Getz G, Basso A, Ye Q, Lobo JM, She Y, Osman I, Golub TR, Sebolt-Leopold J, Sellers WR, Rosen N. BRAF mutation predicts sensitivity to MEK inhibition. Nature. 2006;439:358–362. PMCID: PMC3306236.
2. Janakiraman M, Vakiani E, Zeng Z, Pratilas CA, Taylor BS, Chitale D, Halilovic E, Wilson M, Huberman K, Ricarte Filho JC, Persaud Y, Levine DA, Fagin JA, Jhanwar SC, Mariadason JM, Lash A, Ladanyi M, Saltz LB, Heguy A, Paty PB, Solit DB. Genomic and biological characterization of exon 4 KRAS mutations in human cancer. Cancer Res. 2010;70:5901–5911. PMCID: PMC2943514
3. Nissan MH, Pratilas CA, Jones AM, Ramirez R, Won H, Liu C, Tiwari S, Kong L, Hanrahan AJ, Yao Z, Merghoub T, Ribas A, Chapman PB, Yaeger R, Taylor BS, Schultz N, Berger MF, Rosen N, Solit DB. Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence. Cancer Res. 2014;74:2340–2350. PMCID: PMC4005042.
4. Yao Z, Torres NM, Tao A, Gao Y, Luo L, Li Q, de Stanchina E, Abdel-Wahab O, Solit DB, Poulikakos PI, Rosen N. BRAF Mutants Evade ERK-Dependent Feedback by Different Mechanisms that Determine Their Sensitivity to Pharmacologic Inhibition. Cancer Cell. 2015 Sep 14. Epub 2015 Sep 3. PMID: 26343582. PMCID: PMC4894664.

5. While selective RAF inhibitors have significant clinical activity in patients with BRAF-mutant melanoma, responses are often incomplete, and resistance typically develops. My laboratory has sought to define mechanisms of resistance to RAF and other selective kinase inhibitors. This work has led to ongoing combination clinical trials that have shown promising results in a range of RAF- and RAS-altered tumors.
1. Xing F, Persaud Y, Pratilas CA, Taylor BS, Janakiraman M, She QB, Gallardo H, Liu C, Merghoub T, Hefter B, Dolgalev I, Viale A, Heguy A, De Stanchina E, Cobrinik D, Bollag G, Wolchok J, Houghton A, Solit DB. Concurrent loss of the PTEN and RB1 tumor suppressors attenuates RAF dependence in melanomas harboring V600EBRAF. Oncogene. 2012;31:446–457. PMCID: PMC3267014.
2. Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, Shi H, Atefi M, Titz B, Gabay MT, Salton M, Dahlman KB, Tadi M, Wargo JA, Flaherty KT, Kelley MC, Misteli T, Chapman PB, Sosman JA, Graeber TG, Ribas A, Lo RS, Rosen N, Solit DB. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature. 2011;480:387–390. PMCID: PMC3266695.
3. Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D, Valtorta E, Schiavo R, Buscarino M, Siravegna G, Bencardino K, Cercek A, Chen CT, Veronese S, Zanon C, Sartore-Bianchi A, Gambacorta M, Gallicchio M, Vakiani E, Boscaro V, Medico E, Weiser M, Siena S, Di Nicolantonio F, Solit D†, Bardelli A†. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012;486:532–536. PMCID: PMC3927413. †Co-corresponding authors.
4. Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, Davis A, Mongare MM, Gould J, Frederick DT, Cooper ZA, Chapman PB, Solit DB, Lo RS, Flaherty KT, Ogino S, Wargo JA, Golub TR. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012;26;487:500–504. PMCID: PMC3711467.

Complete List of Published Work in URL to My Bibliography: http://www.ncbi.nlm.nih.gov/pubmed/?term=solit+d