Developmental Therapeutics Program

The DF/HCC Developmental Therapeutics Program fosters the development of new anti-cancer agents by harnessing basic science and the translational and clinical resources of the DF/HCC member institutions. Residing at a key point in the pipeline of discovery, the Program provides the expertise and opportunity through which promising new leads and agents are developed first in Phase I trials and then in Phase II trials, in conjunction with DF/HCC’s disease-based programs.

The Program also serves as an important conduit for the acquisition of agents from the NCI and industry and for those agents transition to Phase II trials in disease-based programs. Increasingly, the Program’s trials seek to establish biomarkers useful in patient selection and in proof of action. It relies on multiple sources of information, including genomic analysis of initial and sequential tumor biopsies, as well as genomic studies of circulating DNA and circulating tumor cells and imaging to determine biomarkers of response and drug resistance. Developmental Therapeutics studies not only define optimal dose and schedule but also incorporate proof-of-mechanism and proof-of-principle endpoints. Currently, the Program has more than 50 members.

Recent Publications

  • Weisberg EL, Schauer NJ, Yang J, Lamberto I, Doherty L, Bhatt S, Nonami A, Meng C, Letai A, Wright R, Tiv H, Gokhale PC, Ritorto MS, De Cesare V, Trost M, Christodoulou A, Christie A, Weinstock DM, Adamia S, Stone R, Chauhan D, Anderson KC, Seo HS, Dhe-Paganon S, Sattler M, Gray NS, Griffin JD, Buhrlage SJ. Inhibition of USP10 induces degradation of oncogenic FLT3. Nat Chem Biol 2017. PubMed
  • Rajabi H, Hiraki M, Tagde A, Alam M, Bouillez A, Christensen CL, Samur M, Wong KK, Kufe D. MUC1-C activates EZH2 expression and function in human cancer cells. Sci Rep 2017; 7:7481. PubMed
  • Pritz JR, Wachter F, Lee S, Luccarelli J, Wales TE, Cohen DT, Coote P, Heffron GJ, Engen JR, Massefski W, Walensky LD. Allosteric sensitization of proapoptotic BAX. Nat Chem Biol 2017; 13:961-967. PubMed
  • Ren JG, Seth P, Ye H, Guo K, Hanai JI, Husain Z, Sukhatme VP. Citrate Suppresses Tumor Growth in Multiple Models through Inhibition of Glycolysis, the Tricarboxylic Acid Cycle and the IGF-1R Pathway. Sci Rep 2017; 7:4537. PubMed
  • Johnson SF, Cruz C, Greifenberg AK, Dust S, Stover DG, Chi D, Primack B, Cao S, Bernhardy AJ, Coulson R, Lazaro JB, Kochupurakkal B, Sun H, Unitt C, Moreau LA, Sarosiek KA, Scaltriti M, Juric D, Baselga J, Richardson AL, Rodig SJ, D'Andrea AD, Balmaña J, Johnson N, Geyer M, Serra V, Lim E, Shapiro GI. CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer. Cell Rep 2016; 17:2367-2381. PubMed
  • Zhu AX, Baron AD, Malfertheiner P, Kudo M, Kawazoe S, Pezet D, Weissinger F, Brandi G, Barone CA, Okusaka T, Wada Y, Park JO, Ryoo BY, Cho JY, Chung HC, Li CP, Yen CJ, Lee KD, Chang SC, Yang L, Abada PB, Chau I. Ramucirumab as Second-Line Treatment in Patients With Advanced Hepatocellular Carcinoma: Analysis of REACH Trial Results by Child-Pugh Score. JAMA Oncol 2016. PubMed
  • Chen B, Zheng B, DeRan M, Jarugumilli GK, Fu J, Brooks YS, Wu X. ZDHHC7-mediated S-palmitoylation of Scribble regulates cell polarity. Nat Chem Biol 2016. PubMed
  • Lee S, Wales TE, Escudero S, Cohen DT, Luccarelli J, Gallagher CG, Cohen NA, Huhn AJ, Bird GH, Engen JR, Walensky LD. Allosteric inhibition of antiapoptotic MCL-1. Nat Struct Mol Biol 2016; 23:600-7. PubMed
  • Hiraki M, Suzuki Y, Alam M, Hinohara K, Hasegawa M, Jin C, Kharbanda S, Kufe D. MUC1-C Stabilizes MCL-1 in the Oxidative Stress Response of Triple-Negative Breast Cancer Cells to BCL-2 Inhibitors. Sci Rep 2016; 6:26643. PubMed
  • Kantar RS, Lashgari G, Tabet EI, Lewandrowski GK, Carvalho LA, Tannous BA. Imaging Tumor Vascularity and Response to Anti-Angiogenic Therapy Using Gaussia Luciferase. Sci Rep 2016; 6:26353. PubMed
  • Gao Y, Shen JK, Choy E, Zhang Z, Mankin HJ, Hornicek FJ, Duan Z. Pharmacokinetics and tolerability of NSC23925b, a novel P-glycoprotein inhibitor: preclinical study in mice and rats. Sci Rep 2016; 6:25659. PubMed
  • Shen JK, Cote GM, Gao Y, Choy E, Mankin HJ, Hornicek FJ, Duan Z. Targeting EZH2-mediated methylation of H3K27 inhibits proliferation and migration of Synovial Sarcoma in vitro. Sci Rep 2016; 6:25239. PubMed
  • Choi YE, Meghani K, Brault ME, Leclerc L, He YJ, Day TA, Elias KM, Drapkin R, Weinstock DM, Dao F, Shih KK, Matulonis U, Levine DA, Konstantinopoulos PA, Chowdhury D. Platinum and PARP Inhibitor Resistance Due to Overexpression of MicroRNA-622 in BRCA1-Mutant Ovarian Cancer. Cell Rep 2016; 14:429-39. PubMed
  • Richardson PG, Jagannath S, Moreau P, Jakubowiak AJ, Raab MS, Facon T, Vij R, White D, Reece DE, Benboubker L, Zonder J, Tsao LC, Anderson KC, Bleickardt E, Singhal AK, Lonial S, . Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: final phase 2 results from the randomised, open-label, phase 1b-2 dose-escalation study. Lancet Haematol 2015; 2:e516-27. PubMed
  • Askoxylakis V, Ferraro GB, Kodack DP, Badeaux M, Shankaraiah RC, Seano G, Kloepper J, Vardam T, Martin JD, Naxerova K, Bezwada D, Qi X, Selig MK, Brachtel E, Duda DG, Huang P, Fukumura D, Engelman JA, Jain RK. Preclinical Efficacy of Ado-trastuzumab Emtansine in the Brain Microenvironment. Journal of the National Cancer Institute 2015. PubMed
  • Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, Bradner JE. DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 2015; 348:1376-81. PubMed
  • Raina D, Uchida Y, Kharbanda A, Rajabi H, Panchamoorthy G, Jin C, Kharbanda S, Scaltriti M, Baselga J, Kufe D. Targeting the MUC1-C oncoprotein downregulates HER2 activation and abrogates trastuzumab resistance in breast cancer cells. Oncogene 2014. PubMed
  • Cottini F, Hideshima T, Xu C, Sattler M, Dori M, Agnelli L, ten Hacken E, Bertilaccio MT, Antonini E, Neri A, Ponzoni M, Marcatti M, Richardson PG, Carrasco R, Kimmelman AC, Wong KK, Caligaris-Cappio F, Blandino G, Kuehl WM, Anderson KC, Tonon G. Rescue of Hippo coactivator YAP1 triggers DNA damage-induced apoptosis in hematological cancers. Nat Med 2014; 20:599-606. PubMed
  • Yin L, Kufe T, Avigan D, Kufe D. Targeting MUC1-C is synergistic with bortezomib in downregulating TIGAR and inducing ROS-mediated myeloma cell death. Blood 2014. PubMed
  • Rajabi H, Alam M, Takahashi H, Kharbanda A, Guha M, Ahmad R, Kufe D. MUC1-C oncoprotein activates the ZEB1/miR-200c regulatory loop and epithelial-mesenchymal transition. Oncogene 2014; 33:1680-9. PubMed
  • Chen Z, Akbay E, Mikse O, Tupper T, Cheng K, Wang Y, Tan X, Altabef A, Woo SA, Chen L, Reibel JB, Janne PA, Sharpless NE, Engelman JA, Shapiro GI, Kung AL, Wong KK. Co-clinical trials demonstrate superiority of crizotinib to chemotherapy in ALK-rearranged non-small cell lung cancer and predict strategies to overcome resistance. Clin Cancer Res 2014; 20:1204-11. PubMed
  • Bandopadhayay P, Bergthold G, Nguyen B, Schubert S, Gholamin S, Tang Y, Bolin S, Schumacher SE, Zeid R, Masoud S, Yu F, Vue N, Gibson WJ, Paolella BR, Mitra SS, Cheshier SH, Qi J, Liu KW, Wechsler-Reya R, Weiss WA, Swartling FJ, Kieran MW, Bradner JE, Beroukhim R, Cho YJ. BET bromodomain inhibition of MYC-amplified medulloblastoma. Clin Cancer Res 2014; 20:912-25. PubMed
  • Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, Wong KK, Bradner JE, Kaelin WG. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 2014; 343:305-9. PubMed
  • Bolli N, Avet-Loiseau H, Wedge DC, Van Loo P, Alexandrov LB, Martincorena I, Dawson KJ, Iorio F, Nik-Zainal S, Bignell GR, Hinton JW, Li Y, Tubio JM, McLaren S, O' Meara S, Butler AP, Teague JW, Mudie L, Anderson E, Rashid N, Tai YT, Shammas MA, Sperling AS, Fulciniti M, Richardson PG, Parmigiani G, Magrangeas F, Minvielle S, Moreau P, Attal M, Facon T, Futreal PA, Anderson KC, Campbell PJ, Munshi NC. Heterogeneity of genomic evolution and mutational profiles in multiple myeloma. Nat Commun 2014; 5:2997. PubMed
  • Wagle N, Van Allen EM, Treacy DJ, Frederick DT, Cooper ZA, Taylor-Weiner A, Rosenberg M, Goetz EM, Sullivan RJ, Farlow DN, Friedrich DC, Anderka K, Perrin D, Johannessen CM, McKenna A, Cibulskis K, Kryukov G, Hodis E, Lawrence DP, Fisher S, Getz G, Gabriel SB, Carter SL, Flaherty KT, Wargo JA, Garraway LA. MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition. 2014; 4:61-8. PubMed
  • Faber AC, Coffee EM, Costa C, Dastur A, Ebi H, Hata AN, Yeo AT, Edelman EJ, Song Y, Tam AT, Boisvert JL, Milano RJ, Roper J, Kodack DP, Jain RK, Corcoran RB, Rivera MN, Ramaswamy S, Hung KE, Benes CH, Engelman JA. mTOR inhibition specifically sensitizes colorectal cancers with KRAS or BRAF mutations to BCL-2/BCL-XL inhibition by suppressing MCL-1. 2014; 4:42-52. PubMed
  • Shapiro GI, Rodon J, Bedell C, Kwak EL, Baselga J, Braña I, Pandya SS, Scheffold C, Laird AD, Nguyen LT, Xu Y, Egile C, Edelman G. Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245408 (XL147), an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. Clin Cancer Res 2014; 20:233-45. PubMed
  • Szlyk B, Braun CR, Ljubicic S, Patton E, Bird GH, Osundiji MA, Matschinsky FM, Walensky LD, Danial NN. A phospho-BAD BH3 helix activates glucokinase by a mechanism distinct from that of allosteric activators. Nat Struct Mol Biol 2014; 21:36-42. PubMed
  • Yasuda H, Park E, Yun CH, Sng NJ, Lucena-Araujo AR, Yeo WL, Huberman MS, Cohen DW, Nakayama S, Ishioka K, Yamaguchi N, Hanna M, Oxnard GR, Lathan CS, Moran T, Sequist LV, Chaft JE, Riely GJ, Arcila ME, Soo RA, Meyerson M, Eck MJ, Kobayashi SS, Costa DB. Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med 2013; 5:216ra177. PubMed
  • Chapuy B, McKeown MR, Lin CY, Monti S, Roemer MG, Qi J, Rahl PB, Sun HH, Yeda KT, Doench JG, Reichert E, Kung AL, Rodig SJ, Young RA, Shipp MA, Bradner JE. Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma. Cancer Cell 2013; 24:777-90. PubMed
  • Akbay EA, Koyama S, Carretero J, Altabef A, Tchaicha JH, Christensen CL, Mikse OR, Cherniack AD, Beauchamp EM, Pugh TJ, Wilkerson MD, Fecci PE, Butaney M, Reibel JB, Soucheray M, Cohoon TJ, Janne PA, Meyerson M, Hayes DN, Shapiro GI, Shimamura T, Sholl LM, Rodig SJ, Freeman GJ, Hammerman PS, Dranoff G, Wong KK. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. 2013. PubMed
  • Huang Y, Stylianopoulos T, Duda DG, Fukumura D, Jain RK. Benefits of vascular normalization are dose and time dependent--letter. Cancer Res 2013; 73:7144-6. PubMed
  • Batchelor TT, Gerstner ER, Emblem KE, Duda DG, Kalpathy-Cramer J, Snuderl M, Ancukiewicz M, Polaskova P, Pinho MC, Jennings D, Plotkin SR, Chi AS, Eichler AF, Dietrich J, Hochberg FH, Lu-Emerson C, Iafrate AJ, Ivy SP, Rosen BR, Loeffler JS, Wen PY, Sorensen AG, Jain RK. Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation. Proc Natl Acad Sci U S A 2013; 110:19059-64. PubMed
  • Johnson N, Johnson SF, Yao W, Li YC, Choi YE, Bernhardy AJ, Wang Y, Capelletti M, Sarosiek KA, Moreau LA, Chowdhury D, Wickramanayake A, Harrell MI, Liu JF, D'Andrea AD, Miron A, Swisher EM, Shapiro GI. Stabilization of mutant BRCA1 protein confers PARP inhibitor and platinum resistance. Proc Natl Acad Sci U S A 2013; 110:17041-6. PubMed
  • Chauhan VP, Martin JD, Liu H, Lacorre DA, Jain SR, Kozin SV, Stylianopoulos T, Mousa AS, Han X, Adstamongkonkul P, Popović Z, Huang P, Bawendi MG, Boucher Y, Jain RK. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat Commun 2013; 4:2516. PubMed
  • Emblem KE, Mouridsen K, Bjornerud A, Farrar CT, Jennings D, Borra RJ, Wen PY, Ivy P, Batchelor TT, Rosen BR, Jain RK, Sorensen AG. Vessel architectural imaging identifies cancer patient responders to anti-angiogenic therapy. Nat Med 2013; 19:1178-83. PubMed
  • Stroopinsky D, Rosenblatt J, Ito K, Mills H, Yin L, Rajabi H, Vasir B, Kufe T, Luptakova K, Arnason J, Nardella C, Levine JD, Joyce RM, Galinsky I, Reiter Y, Stone RM, Pandolfi PP, Kufe D, Avigan D. MUC1 is a potential target for the treatment of acute myeloid leukemia stem cells. Cancer Res 2013; 73:5569-79. PubMed
  • Zhang YX, van Oosterwijk JG, Sicinska E, Moss S, Remillard SP, van Wezel T, Bühnemann C, Hassan AB, Demetri GD, Bovée JV, Wagner AJ. Functional profiling of receptor tyrosine kinases and downstream signaling in human chondrosarcomas identifies pathways for rational targeted therapy. Clin Cancer Res 2013; 19:3796-807. PubMed
  • Rosenblatt J, Avivi I, Vasir B, Uhl L, Munshi NC, Katz T, Dey BR, Somaiya P, Mills H, Campigotto F, Weller E, Joyce R, Levine JD, Tzachanis D, Richardson P, Laubach J, Raje N, Boussiotis V, Yuan YE, Bisharat L, Held V, Rowe J, Anderson K, Kufe D, Avigan D. Vaccination with dendritic cell/tumor fusions following autologous stem cell transplant induces immunologic and clinical responses in multiple myeloma patients. Clin Cancer Res 2013; 19:3640-8. PubMed
  • Floyd SR, Pacold ME, Huang Q, Clarke SM, Lam FC, Cannell IG, Bryson BD, Rameseder J, Lee MJ, Blake EJ, Fydrych A, Ho R, Greenberger BA, Chen GC, Maffa A, Del Rosario AM, Root DE, Carpenter AE, Hahn WC, Sabatini DM, Chen CC, White FM, Bradner JE, Yaffe MB. The bromodomain protein Brd4 insulates chromatin from DNA damage signalling. Nature 2013; 498:246-50. PubMed
  • Socinski MA, Goldman J, El-Hariry I, Koczywas M, Vukovic V, Horn L, Paschold E, Salgia R, West H, Sequist LV, Bonomi P, Brahmer J, Chen LC, Sandler A, Belani CP, Webb T, Harper H, Huberman M, Ramalingam S, Wong KK, Teofilovici F, Guo W, Shapiro GI. A multicenter phase II study of ganetespib monotherapy in patients with genotypically defined advanced non-small cell lung cancer. Clin Cancer Res 2013; 19:3068-77. PubMed
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