Publications and Success Stories

Research supported by the Center for Precision Disease Modeling has led to numerous publications in high-profile journals.

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PKLR promotes colorectal cancer liver colonization through induction of glutathione synthesis (Nguyen, A. et al J Clin Invest. 2016)

Key takeaways:

  • PKLR expression is upregulated in human colorectal cancer liver metastases and is associated with metastatic outcomes in primary tumors
  • Targeting of glutathione synthesis as a therapeutic strategy

Metastatic Latency and Immune Evasion through Autocrine Inhibition of WNT (Malladi, S. et al Cell 2016)

Key takeaways:

  • Latent metastasis model: Latency Competent Cancer Cells (LCC), isolated by in vivo selection of human cell populations in mice represent a distinct class of stem-like cells primed to enter quiescence and evade innate immunity
  • LCC cells associated with the vasculature can enter proliferative quiescence and downregulate the expression of cell surface NK sensors to evade immune surveillance. Surviving latent metastatic cells may evolve and eventually outbreak to form macrometastases

Deriving human ENS lineages for cell therapy and drug discovery in Hirschsprung disease (Fattahi, F. et al Nature 2016)

Key takeaways:

  • Defects in the enteric nervous system (ENS) development are responsible for many human disorders including Hirschsprung disease (HSCR)
  • HSCR is caused by the developmental failure of ENS progenitors to migrate into the gastrointestinal tract, particularly the distal colon.
  • The in vivo engraftment and migration of human PS-cell-derived ENS precursors rescue disease-related mortality in HSCR mice

BRAF Mutants Evade ERK-Dependent Feedback by Different Mechanisms that Determine Their Sensitivity to Pharmacologic Inhibition (Zhan, Y. et al Cancer Cell 2015)

Key takeaways:

  • ERK signaling requires RAS-induced RAF dimerization and is limited by feedback
  • Activating BRAF mutants are RAS independent and signal as active monomers or constitutive dimers
  • RAF dimers are insensitive to clinical RAF inhibitors due to negative cooperativity
  • A compound that equally inhibits mutant BRAF monomers and dimers overcomes resistance

Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor (Rodrik-Outmezguine, V. et al Nature 2016)

Key takeaway:

  • Development of a new class of mTOR inhibitors that overcomes resistance to existing first- and second-generation inhibitors

Modified CAR-T cells show enhanced therapeutic activity against xenografted lymphomas (Boice, M. et al Cell 2016)

Key takeaways:

  • The interaction between HVEM and BTLA is lost in most follicular lymphomas
  • Soluble HVEM restores the inhibitory BTLA signal
  • CAR-T cells that produce solHVEM are active against lymphoma

SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer (Mu, P. et al Science 2017)

Key takeaways:

  • Prostate tumors can develop resistance to enzalutamide by a phenotypic shift from androgen receptor (AR)–dependent luminal epithelial cells to AR-independent basal-like cells.
  • This can be reversed by restoring TP53 and RB1 function or by inhibiting SOX2 expression

A combinatorial strategy for treating KRAS-mutant lung cancer (Manchado, E. et al Nature 2016)

Key takeaways:

  • Trametinib treament of KRAS-mutant lung tumors provokes a compensatory response involving FGFR1 signaling that leads to adaptive drug resistance
  • Suppression of FGFR1 in combination with Trametinib leads to tumor regression of KRAS-mutant lung tumors

A Damage-Independent Role for 53BP1 that Impacts Break Order and Igh Architecture during Class Switch Recombination (Rocha, P. et al Cell Rep 2016)

Key takeaways:

  • 53BP1 is essential for preferential targeting of the upstream switch region
  • 53BP1’s absence results in increased interaction frequency between switch regions
  • Alterations in switch region targeting and locus architecture impact CSR
  • 53BP1’s action is independent of its role in the double-strand break repair pathway

KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer (Burgess, MR. et al Cell 2017)

Key takeaway:

  • Allelic imbalance of the KRAS mutant and wildtype alleles dictates the trade-off between cancer cell growth and MEK inhibitor response and resistance

A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors (Drilon, A. et al Cancer Discov 2017)

Key takeaway:

  • Developing novel pharmacokinetics (PK)-guided clinical trial designs that accelerate the development of next-generation TRK inhibitors that can overcome mechanisms of resistance to first-generation drugs

The Mre11-Nbs1 Interface Is Essential for Viability and Tumor Suppression (Kim, JH. et al Cell Rep 2017)

Key takeaways:

  • TALEN editing used to generate Nbs1mid mutant mice altered the Mre11 interaction
  • The Mre11-Nbs1 interaction is essential for embryonic viability and DDR
  • The Nbs1 minimal fragment (108 amino acid) is sufficient to sustain viability
  • Nbs1 is required for proper assembly and localization of Mre11 and Rad50

Combination Targeted Therapy to Disrupt Aberrant Oncogenic Signaling and Reverse Epigenetic Dysfunction in IDH2- and TET2-Mutant Acute Myeloid Leukemia (Shih, AH. et al Cancer Discov 2017)

Key takeaways:

  • We demonstrated the efficacy of AG-221, a first in class IDH2 inhibitor in AML models
  • We demonstrated combination efficacy of FLT3 inhibition combined with IDH2 inhibition or hypomethylating agents in IDH2/TET2 mutant AML

Tumors with class 3 BRAF mutants are sensitive to the inhibition of activated RAS (Yao, Z. et al Nature 2017)

Key takeaways:

  • We have defined three distinct functional classes of BRAF mutants in human tumors.
  • The mutants activate ERK signaling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.
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Yao Z, Yaeger R, Tao A, Torres N, Chang M, Drosten M, Zhao H, Miles L, Campbell N, de Stanchina E, Solit D, Barbacid M, Taylor B, Rosen N. (2017). “Tumors with class 3 BRAF mutants are RAS dependent and sensitive to its inhibition”. Nature 548:234-238

Xue Y, Martelotto L, Baslan T, Vides A, Solomon M, Mai TT, Chaudhary N, Riely GJ, Li BT, Scott K, Cechhi F, Stierner U, Chadalavada K, de Stanchina E, Schwartz S, Hembrough T, Nanjangud G, Berger MF, Nilsson J, Lowe SW, Reis-Filho JS, Rosen N, Lito P. (2017). “An approach to suppress the evolution of resistance in BRAFV600E-mutant cancer”. Nat Med 23:929-937

Henssen AG, Koche R, Zhuang J, Jiang E, Reed C, Eisenberg A, Still E, Rodríguez-Fos E, Gonzalez S, Puiggròs M, Blackford A, Mason C, de Stanchina E, Gönen M, Emde AK, Shah M, Aurora K, Socci N, Perlman E, Antonescu C, Roberts CW, Steen Mullen E, Jackson Torrents D, Weng A, Armstrong SA, Kentsis A. (2017) “Human PGBD5 DNA transposase promotes site-specific oncogenic mutations in rhabdoid tumors” Nat Genetics 49:1005-1014

O’Rourke, KP. Loizou, E, Livshits, G, Schatoff EM, Baslan T, Manchado E, Simon J, Romesser P, Leach B, Han T, Pauli C, Beltran H, Rubin M, Dow LE, Lowe SW.  “Transplantation of engineered organoids enables rapid generation of metastatic models of colorectal cancer”. Nature Biotechnol 35:577-582

Drilon A, Nagasubramanian R, Blake JF, Ku N, Tuch BB, Ebata K, Smith S, Lauriault V, Kolakowski GR, Brandhuber BJ, Larsen PD, Bouhana KS, Winski SL, Hamor R, Wu WI, Parker A, Morales TH, Sullivan FX, DeWolf WE, Wollenberg LA, Gordon PR, Douglas-Lindsay DN, Scaltriti M, Benayed R, Raj S, Hanusch B, Schram AM, Jonsson P, Berger MF, Hechtman JF, Taylor BS, Andrews S, Rothenberg SM, Hyman DM (2017). “A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors”. Cancer Discov. 7:963-972

Hyman DM, Taylor BS, Baselga J. (2017). “Implementing genome-driven oncology”. Cell 168:584-99 PMID: 28187282

Burgess MR, Hwang E, Mroue R, Bielski CM, Wandler AM, Huang B, Firestone AJ, Young A, LaCap JA, Crocker J, Asthana S, Davis EM, Xu Jin, Akagi K, Le Beau MM, Li Q, Haley B, Stokoe D, Sampath D, Taylor BS, Evangelista M, Shannon K. (2017). “KRAS allelic imbalance enhances fitness and modulates MEK dependence in KRAS mutant cancers”. Cell 168:817-829 PMID: 28215705

Shih AH, Meydan C, Shank K, Garrett-Bakelman FE, Ward PS, Intlekofer AM, Nazir A, Stein EM, Knapp K, Glass J, Travins J, Straley K, Gliser C, Mason CE, Yen K, Thompson CB, Melnick A, Levine RL (2017). “Combination Targeted Therapy to Disrupt Aberrant Oncogenic Signaling and Reverse Epigenetic Dysfunction in IDH2- and TET2-Mutant Acute Myeloid Leukemia”. Cancer Discov. 2017 Apr 13. 7:494-505 PMID: 28408400

Mondello P, Brea EJ, de Stanchina E, Toska E, Chang AY, Fennell M, Seshan V, Garippa R, Scheinberg DA, Baselga J, Wendel HG, Younes A (2017).  “Panobinostat acts synergistically with ibrutinib in diffuse large B cell lymphoma cells with MyD88 L265 mutations” JCI Insight: 2:e90196. PMID: 28352655

Price EW, Carnazza KE, Carlin SD, Cho A, Edwards KJ, Sevak KK, Glaser JM, de Stanchina E, Janjigian YY, Lewis JS (2017). “89Zr-DFO-AMG102 Immuno-PET to Determine Local HGF Protein Levels in Tumors for Enhanced Patient Selection.” J Nucl Med 58:1386-1394 PMID: 28280216

Gardner EE, Lok BH, Schneeberger VE, Desmeules P, Miles LA, Arnold PK, Ni A, Khodos I, de Stanchina E, Nguyen T, Sage J, Campbell JE, Ribich S, Rekhtman N, Dowlati A, Massion PP, Rudin CM, Poirier JT (2017). “Chemosensitive Relapse in Small Cell Lung Cancer Proceeds through an EZH2-SLFN11 Axis”. Cancer Cell 31:286-299. PMID: 28196596

Nemec AA, Abriola L, Merkel JS, de Stanchina E, DeVeaux M, Zelterman D, Glazer PM, Sweasy J (2017). “DNA Polymerase Beta Germline Variant Confers Cellular Response to Cisplatin Therapy.” Mol Cancer Res 15:269-280 PMID: 28074003

Mondello P, Derenzini E, Asgari A, Philip J, Brea EJ, Seshan V, Hendrickson RC, de Stanchina E, Scheinberg DA, Younes A (2017). “Dual Inhibition of Histone Deacetylases and Phosphoinositide 3-kinase enhances Therapeutic Activity Against B Cell Lymphoma.” Oncotarget 8:14017-14028 PMID: 28147336

Mu P, Zhang Z, Bebelli M, Karthaus W, Hoover E, Wongvipat J,  Ku S, Chen, Gao D, Cao Z, Shah N, Adams E, Abida W, Watson PA, Huang CH, de Stanchina E, Lowe S, Ellis L, Beltran H, Rubin MA, Goodrich D, Demichelis F, Sawyers CL (2017). “SOX2 promotes lineage plasticity and antiandrogen resistance in TP53 mutant prostate cancer”. Science 355: 84-88 PMID: 28059768

Lok BH, Gardner EE, SchneebergerVE, Ni A, Desmeules P, RekhtmanN, de Stanchina E, TeicherBA, Riaz R,Powell SN, Poirier JT, Rudin CM (2017). “PARP Inhibitor Activity Correlates with SLFN11 Expression and Demonstrates Synergy with Temozolomide in Small Cell Lung Cancer.” Clin Cancer Res 23:523-535 PMID: 27440269

Kim JH, Grosbart M, Anand R, Wyman C, Cejka P, Petrini JH. (2017) “The Mre11-Nbs1 Interface Is Essential for Viability and Tumor Suppression”. Cell Rep. 18:496-507

O’Rourke, K.P., Ackerman, S., Dow, L.E., and Lowe, S.W. (2016). “Immunofluorescent Staining of Mouse Intestinal Stem Cells”. Bio Protoc. 6(4). pii: e1732 PMCID: PMC4996654.

 O’Rourke, K.P., Dow, L.E., and Lowe, S.W. (2016) “Isolation, Culture, and Maintenance of Mouse Intestinal Stem Cells”. Bio Protoc. 6(4). pii: e1733 PMCID: PMC4996657

Rocha PP, Raviram R, Fu Y, Kim J, Luo VM, Aljoufi A, Swanzey E, Pasquarella A, Balestrini A, Miraldi ER, Bonneau R, Petrini J, Schotta G, Skok JA. (2016). “A Damage-Independent Role for 53BP1 that Impacts Break Order and Igh Architecture during Class Switch Recombination” Cell Rep 16:48-55.

Balestrini A, Nicolas L, Yang-Lott K, Guryanova OA, Levine RL, Bassing CH, Chaudhuri J, Petrini JH. (2016). “Defining ATM-Independent Functions of the Mre11 Complex with a Novel Mouse Model”. Mol Cancer Res. 14:185-95.

Mattar M, Abdel-Wahab O, de Stanchina E (2016) “Acquisition and storage of clinical samples to establish PDX models” (book chapter). Patient Derived Tumor Xenograft (PDX) Models – Promise, Potential and Practice, Elsevier Press: 109-118

Mattar M, Abdel-Wahab O, Poirier JT, Scaltriti M, de Stanchina E (2016) “Methodologies for developing and maintaining PDX mouse models” (book chapter). Patient Derived Tumor Xenograft (PDX) Models – Promise, Potential and Practice, Elsevier Press: 119-134

Krivtsov A, Mattar M, Uthamanthil RK and de Stanchina E (2016) “Running a PDX Core Support Program” (book chapter). Patient Derived Tumor Xenograft (PDX) Models – Promise, Potential and Practice, Elsevier Press: 161-172

Inghirami G, Tinkey PT, de Stanchina E and Uthamanthil RK (2016). “Patient Derived Tumor Xenograft: present and future challenges and applications” (book chapter). Patient Derived Tumor Xenograft (PDX) Models – Promise, Potential and Practice, Elsevier Press: 429-451