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 vitroand 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.
Please contact Dr. Porter about postdoctoral fellowship positions that are currently open or view the posting.
Jodi Dougan, Lead Research Specialist
Chengjing Zhou, Senior Research Specialist
Rizvan Uluisik, PhD, Postdoctoral Research Fellow
Jairo Fonseca, MD, Postdoctoral Fellow
Alisha "Rae" Hunter, Graduate Student
Claire Pillsbury, Graduate Student
Camille David, Graduate Student
Garcia TB, Fosmire SP, Porter CC. Increased activity of both CDK1 and CDK2 is necessary for the combinatorial activity of WEE1 inhibition and cytarabine. Leuk Res. 2018 Jan;64:30-33. doi: 10.1016/j.leukres.2017.11.004. Epub 2017 Nov 11. PubMed PMID: 29175378; PubMed Central PMCID: PMC5929465.
Ellison MA, Gearheart CM, Porter CC, Ambruso DR. IFN-γ alters the expression of diverse immunity related genes in a cell culture model designed to represent maturing neutrophils. PLoS One. 2017 Oct 5;12(10):e0185956. doi:10.1371/journal.pone.0185956. eCollection 2017. PubMed PMID: 28982143; PubMedCentral PMCID: PMC5628906.
Kalish JM, Doros L, Helman LJ, Hennekam RC, Kuiper RP, Maas SM, Maher ER, Nichols KE, Plon SE, Porter CC, Rednam S, Schultz KAP, States LJ, Tomlinson GE, Zelley K, Druley TE. Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma. Clin Cancer Res. 2017 Jul 1;23(13):e115-e122. doi: 10.1158/1078-0432.CCR-17-0710. Review. PubMed PMID: 28674120; PubMed Central PMCID: PMC5538793.
Achatz MI, Porter CC, Brugières L, Druker H, Frebourg T, Foulkes WD, Kratz CP, Kuiper RP, Hansford JR, Hernandez HS, Nathanson KL, Kohlmann WK, Doros L, Onel K, Schneider KW, Scollon SR, Tabori U, Tomlinson GE, Evans DGR, Plon SE. Cancer Screening Recommendations and Clinical Management of Inherited Gastrointestinal Cancer Syndromes in Childhood. Clin Cancer Res. 2017 Jul 1;23(13):e107-e114. doi:10.1158/1078-0432.CCR-17-0790. Review. PubMed PMID: 28674119.
Garcia TB, Snedeker JC, Baturin D, Gardner L, Fosmire SP, Zhou C, Jordan CT, Venkataraman S, Vibhakar R, Porter CC. A Small-Molecule Inhibitor of WEE1, AZD1775, Synergizes with Olaparib by Impairing Homologous Recombination and Enhancing DNA Damage and Apoptosis in Acute Leukemia. Mol Cancer Ther. 2017 Oct;16(10):2058-2068. doi: 10.1158/1535-7163.MCT-16-0660. Epub 2017 Jun 27. PubMed PMID: 28655785; PubMed Central PMCID: PMC5628125.
Walsh MF, Chang VY, Kohlmann WK, Scott HS, Cunniff C, Bourdeaut F, Molenaar JJ, Porter CC, Sandlund JT, Plon SE, Wang LL, Savage SA. Recommendations for Childhood Cancer Screening and Surveillance in DNA Repair Disorders. Clin Cancer Res. 2017 Jun 1;23(11):e23-e31. doi: 10.1158/1078-0432.CCR-17-0465. Review. PubMed PMID: 28572264; PubMed Central PMCID: PMC5697784.
Porter CC, Druley TE, Erez A, Kuiper RP, Onel K, Schiffman JD, Wolfe Schneider K, Scollon SR, Scott HS, Strong LC, Walsh MF, Nichols KE. Recommendations for Surveillance for Children with Leukemia-Predisposing Conditions. Clin Cancer Res. 2017 Jun 1;23(11):e14-e22. doi: 10.1158/1078-0432.CCR-17-0428. Review. PubMedPMID: 28572263.
Dimberg LY, Towers CG, Behbakht K, Hotz TJ, Kim J, Fosmire S, Porter CC, Tan AC, Thorburn A, Ford HL. A Genome-Wide Loss-of-Function Screen Identifies SLC26A2 as a Novel Mediator of TRAIL Resistance. Mol Cancer Res. 2017 Apr;15(4):382-394. doi: 10.1158/1541-7786.MCR-16-0234. Epub 2017 Jan 20. PubMed PMID: 28108622; PubMed Central PMCID: PMC5380511.
Porter CC. Germ line mutations associated with leukemias. Hematology Am Soc Hematol Educ Program. 2016 Dec 2;2016(1):302-308. Review. PubMed PMID: 27913495.
Gari HH, Gearheart CM, Fosmire S, DeGala GD, Fan Z, Torkko KC, Edgerton SM, Lucia MS, Ray R, Thor AD, Porter CC, Lambert JR. Genome-wide functional genetic screen with the anticancer agent AMPI-109 identifies PRL-3 as an oncogenic driver in triple-negative breast cancers. Oncotarget. 2016 Mar 29;7(13):15757-71. doi:10.18632/oncotarget.7462. PubMed PMID: 26909599; PubMed Central PMCID: PMC4941275.
A complete list of my publications can be found here.
R01 CA172385 (7/1/2013-4/30/2019 (NCE))
Validation and Development of WEE1 as a therapeutic target in AML
Goals: The major goals of this project are to 1) determine whether Wee1 contributes to leukemogenesis, 2) confirm the efficacy and tolerability of cytarabine and WEE1 inhibition in vivo, and 3) identify the mechanism of enhanced AML cell killing with cytarabine and WEE1.
Note: We will apply for a no cost extension of this grant.
Winship Invest$ Pilot Grant (4/1/2017-9/30/2018)
Winship Cancer Institute
The function of ETV6 in B lymphopoiesis
Goals: The major goals of this project are to 1) 1) determine the changes in gene expression patterns in hematopoietic stem and progenitor cells due to ETV6 dysfunction and 2) define the ETV6-dependent architecture of transcription regulatory elements in hematopoietic progenitors.
Scholar Hope Grant (12/31/17-12/30/19)
Hyundai Hope On Wheels Foundation
Targeting effectors of calcineurin-mediated immune evasion to treat leukemia
Goals: The major goals of this project are to 1) determine whether S15 is responsible for immune evasion during leukemia development and 2) determine whether this S15 is expressed on human leukemia cells.