The goal of the Porter lab is to develop novel therapeutic strategies for leukemia through better understanding of molecular mechanisms of leukemogenesis and treatment resistance. We employ a wide variety of techniques, in vitro and in vivo, for discovery and validation of molecular vulnerabilities in cancer cells. For example, using a genome-scale shRNA screen, we identified WEE1 as a chemosensitizing target in AML cells. Subsequent studies funded by the NCI have validated this finding and supported the development of a clinical trial testing a WEE1 inhibitor in children with relapsed/refractory AML. More recently, we have discovered a novel function for the transcription factor ETV6 in regulating normal B cell development, and will test whether and how Etv6 mutation promotes leukemogenesis using a new mouse model with a point mutation in Etv6. A third project in the lab is directed at understanding mechanisms of immune evasion during leukemogenesis.

Despite dramatic improvements in survival for children with leukemia over the last few decades, novel therapeutic strategies are urgently needed for groups of patients with high-risk forms of the disease. While targeting “driver” mutations may improve outcomes for some patients, identifying those patients is a practical challenge and remains formally untested in the vast majority of cases. Even considering the exception of BCR-ABL1+ childhood acute lymphoblastic leukemia, successful treatment with tyrosine kinase inhibition still requires combination with highly toxic conventional chemotherapy, and targeted agents have yet to prove effective in childhood AML. Thus, major advances in outcomes for patients with leukemia require a greater understanding of the molecular and cellular mechanisms of leukemogenesis and treatment resistance. To this end, the Porter lab has three major projects, employing several models of leukemia in vitro and in vivo:

Development and validation of WEE1 as a therapeutic target in acute leukemia

Using a genome-scale shRNA screen, we identified WEE1 as a chemosensitizing target in AML cells exposed to cytarabine (Porter et al, Leukemia, 2012). In NCI funded studies, my lab has subsequently demonstrated that inhibiting WEE1 sensitizes AML and lung cancer cells to anti-metabolite chemotherapeutics independent of the functionality of P53 (Van Linden et al, Mol Cancer Ther, 2012). We have also demonstrated that WEE1 inhibition abrogates the S phase arrest and enhances apoptosis induced by cytarabine. Moreover, using a WEE1 inhibitor in clinical development, we have shown that WEE1 inhibition plus cytarabine enhances disease control and prolongs survival in mice with AML or ALL, including xenografts, better than cytarabine alone (Ford et al, Oncotarget, 2015). These data have led to a clinical trial that is in development (NCT02791919). Ongoing studies are designed toward understanding the mechanisms of chemo-sensitization with WEE1 inhibition, novel functions of WEE1 kinase, and rational combination of WEE1 inhibition with targeted agents.

The role of ETV6 in B lymphopoiesis and leukemogenesis

Consistent with our clinical interest in Cancer Predisposition Syndromes, and in collaboration with colleagues locally and internationally, we recently identified a novel syndrome in which affected family members have thrombocytopenia and predisposition to develop acute lymphoblastic leukemia due to germline mutations in ETV6 (Noetzli et al, Nat Genet, 2015). While rearrangements and mutations in ETV6 are common in ALL, we were among the first to define this new leukemia predisposition syndrome. This work underscores the value of screening the genome in kindreds with cancer to identify novel cancer predisposition mutations that may lead to better mechanistic understanding of oncogenesis. Indeed, new experiments are revealing a novel mechanistic role for ETV6 in lymphopoiesis. Ongoing studies are designed to 1) determine whether normal ETV6 function is necessary for coordinated regulation of transcription factors that drive B lymphopoiesis, 2) determine whether ETV6 is required for normal B cell development and 3) determine whether ETV6 dysfunction promotes leukemogenesis. 

Mechanisms of immune evasion during leukemogenesis

While evasion of the immune system is considered one of the defining features of cancer, the mechanisms by which leukemia cells evade immune detection and elimination remain incompletely understood. We have developed a new leukemia model that is susceptible to immune clearance, with which we can study mechanisms of immune evasion during leukemognesis. With this model, leukemia cells engraft in syngeneic, immune-competent recipient mice, but are rapidly suppressed to remission. Transplantation into immune-deficient mice abrogates remission. We see significant alteration of T cell subsets, including fewer regulatory T cells, in the recipients of this leukemia as compared to controls. In the leukemia cells, we see an altered transcriptional profile, with pro-inflammatory features, and a corresponding increase in secreted chemokines. Ongoing studies are designed to determine the immune cell sub-types responsible for successful leukemia-cell surveillance and suppression and to determine the molecular mechanisms of immune evasion during leukemogenesis.

  • Porter CC, Baturin DA, Choudhary R, DeGregori J. The relative fitness of hematopoietic progenitor cells influences leukemia progression. Leukemia, 2011, 25(5): 891-5. PMID: 21331070
  • Porter CC, Kim J, Fosmire S, Gearheart CM, van Linden A, Baturin DA, Zaberezhnyy V, Gao D, Tan AC, DeGregori J. Integrated genomic analyses identify WEE1 as a critical mediator of cell fate and novel therapeutic target in acute myeloid leukemia. Leukemia, 2012, 26(6): 1266-76. PMID: PMID: 22289989.
  • Sullivan KD, Padilla-Just N, Henry RE, Porter CC, Kim J, Tentler J, Eckhardt G, Tan AC, DeGregori J, Espinosa JM. A genetic screen identifies chemical strategies to manipulate cell fate choice upon p53 activation. Nat Chem Biol, 2012, 8(7): 646-54. PMID: 22660439.
  • Casas-Selves M, Kim J, Zhang Y, Helfrich BA, Gao D, Porter CC, Bunn PA, Chan DC, Tan AC, DeGregori J. Genome wide shRNA screens reveal that the canonical Wnt pathway protects lung cancer cells from EGFR inhibition. Cancer Research, 2012, 72(16): 4154-64. PMID: 22738915.
  • Choudhary R, Baturin D, Freed B, Porter CC. Knockdown of HPRT for selection of genetically modified human hematopoietic progenitor cells. PLoS One, 2013, 8(3):e59594. PMID: 23555045.
  • Van Linden AA, Baturin D, Gardner L, Fosmire SP, Korch C, Reigan P, Porter CC. Inhibition of Wee1 sensitizes cancer cells to anti-metabolite chemotherapeutics independent of p53 functionality. Molecular Cancer Therapeutics, 2013, 12(12): 2675-84. PMID: 24121103.
  • Gore L, DeGregori J, Porter CC. Targeting developmental pathways in children with cancer: what price success? (Invited Review). The Lancet Oncology, 2013, 14(2): e70-8. PMID: 23369685
  • Maycotte P, Gearheart CM, Barnard R, Aryal S, Mulcahy-Levy JM, Fosmire SP, Hansen RJ, Morgan MJ, Porter CC, Gustafson DL, Thorburn A. STAT-3-mediated autophagy dependence identifies subtypes of breast cancer where autophagy inhibition can be efficacious. Cancer Research, 2014, 74(9): 2579-90. PMID: 24590058.
  • Gardner LA, Klawitter J, Gregory MA, Zaberezhnyy V, Baturin D, Christians U, Pollyea DA, Gore L, DeGregori J, Porter CC. Inhibition of calcineurin combined with dasatinib has direct and indirect anti-leukemia effects against BCR-ABL1+ leukemia. Am J Hematol, 2014, 89(9): 896-903. PMID: 24891015.
  • Noetzli L, Lo RW, Lee-Sherick AB, Callaghan M, Noris P, Savoia A, Rajpurkar M, Jones K, Gowan K, Balduini C, Pecci A, Gnan C, De Rocco D, Doubek M, Li L, Lu L, Leung R, Landolt-Marticorena C, Hunger SP, Heller P, Gutierrez-Hartman A, Liang X, Pluthero F, Rowley JW, Weyrich AS, Kahr WHA*, Porter CC* and Di Paola J*. Germline mutations in ETV6 are associated with thrombocytopenia, macrocytosis and predisposition to lymphoblastic leukemia. Nature Genetics, 2015, 47(5): 535-8. PMID 25807284.
  • Ford JB, Baturin D, Burleson TM, Van Linden AA, Kim YM, Porter CC. AZD1775 sensitizes T cell acute lymphoblastic leukemia to cytarabine by promoting apoptosis over DNA repair. Oncotarget, 2015, 6(29):28001-10. PMID 26334102
  • Jones CL, Gearheart CM, Fosmire S, Delgado-Martin C, Evensen NA, Bride K, Waanders AJ, Pais F, Wang J, Bhatla T, Bitterman DS, deRijk S, Bourgeois W, Dandekar S, Park E, Burleson TM, Madhusoodhan PP, Teachey DT, Raetz E, Hermiston ML, Muschen M, Loh M, Hunger SP, Zhang J, Garabedian MJ, Porter CC, Carroll WL. MAPK Signaling Cascades Mediate Distinct Glucocorticoid Resistance Mechanisms in Pediatric Leukemia.  Blood, 2015, 126(19):2201-12. PMID 26324703

A complete list of my publications can be found here.

Please contact Dr. Porter about postdoctoral fellowship positions that are currently open or view the posting