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