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Panka, David

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Panka

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David

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Panka, David
Author's Publications: search.filters.isAuthorOfPublication.66b18df6-8d95-4a94-83ae-2cd6b0190145

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    Clinical Profiling of BCL-2 Family Members in the Setting of BRAF Inhibition Offers a Rationale for Targeting De Novo Resistance Using BH3 Mimetics
    (Public Library of Science, 2014) Frederick, Dennie T.; Salas Fragomeni, Roberto A.; Schalck, Aislyn; Ferreiro-Neira, Isabel; Hoff, Taylor; Cooper, Zachary A.; Haq, Rizwan; Panka, David; Kwong, Lawrence N.; Davies, Michael A.; Cusack, James; Flaherty, Keith; Fisher, David; Mier, James; Wargo, Jennifer A.; Sullivan, Ryan J.
    While response rates to BRAF inhibitiors (BRAFi) are high, disease progression emerges quickly. One strategy to delay the onset of resistance is to target anti-apoptotic proteins such as BCL-2, known to be associated with a poor prognosis. We analyzed BCL-2 family member expression levels of 34 samples from 17 patients collected before and 10 to 14 days after treatment initiation with either vemurafenib or dabrafenib/trametinib combination. The observed changes in mRNA and protein levels with BRAFi treatment led us to hypothesize that combining BRAFi with a BCL-2 inhibitor (the BH3-mimetic navitoclax) would improve outcome. We tested this hypothesis in cell lines and in mice. Pretreatment mRNA levels of BCL-2 negatively correlated with maximal tumor regression. Early increases in mRNA levels were seen in BIM, BCL-XL, BID and BCL2-W, as were decreases in MCL-1 and BCL2A. No significant changes were observed with BCL-2. Using reverse phase protein array (RPPA), significant increases in protein levels were found in BIM and BID. No changes in mRNA or protein correlated with response. Concurrent BRAF (PLX4720) and BCL2 (navitoclax) inhibition synergistically reduced viability in BRAF mutant cell lines and correlated with down-modulation of MCL-1 and BIM induction after PLX4720 treatment. In xenograft models, navitoclax enhanced the efficacy of PLX4720. The combination of a selective BRAF inhibitor with a BH3-mimetic promises to be an important therapeutic strategy capable of enhancing the clinical efficacy of BRAF inhibition in many patients that might otherwise succumb quickly to de novo resistance. Trial Registrations: ClinicalTrials.gov NCT01006980; ClinicalTrials.gov NCT01107418; ClinicalTrials.gov NCT01264380; ClinicalTrials.gov NCT01248936; ClinicalTrials.gov NCT00949702; ClinicalTrials.gov NCT01072175
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    Novel drugs that target the metabolic reprogramming in renal cell cancer
    (BioMed Central, 2016) van der Mijn, Johannes C.; Panka, David; Geissler, Andrew K.; Verheul, Henk. M.; Mier, James
    Molecular profiling studies of tumor tissue from patients with clear cell renal cell cancer (ccRCC) have revealed extensive metabolic reprogramming in this disease. Associations were found between metabolic reprogramming, histopathologic Fuhrman grade, and overall survival of patients. Large-scale genomics, proteomics, and metabolomic analyses have been performed to identify the molecular players in this process. Genes involved in glycolysis, the pentose phosphate pathway, glutamine metabolism, and lipogenesis were found to be upregulated in renal cell cancer (RCC) specimens as compared to normal tissue. Preclinical research indicates that mutations in VHL, FBP1, and the PI3K-AKT-mTOR pathway drives aerobic glycolysis through transcriptional activation of the hypoxia-inducible factors (HIF). Mechanistic studies revealed glutamine as an important source for de novo fatty acid synthesis through reductive carboxylation. Amplification of MYC drives reductive carboxylation. In this review, we present a detailed overview of the metabolic changes in RCC in conjunction with potential novel therapeutics. We discuss preclinical studies that have investigated targeted agents that interfere with various aspects of tumor cell metabolism and emphasize their impact specifically on glycolysis, lipogenesis, and tumor growth. Furthermore, we describe a number of phase 1 and 2 clinical trials that have been conducted with these agents.
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    Effects of HDM2 antagonism on sunitinib resistance, p53 activation, SDF-1 induction, and tumor infiltration by CD11b+/Gr-1+ myeloid derived suppressor cells
    (BioMed Central, 2013) Panka, David; Liu, Qingjun; Geissler, Andrew K; Mier, James
    Background: The studies reported herein were undertaken to determine if the angiostatic function of p53 could be exploited as an adjunct to VEGF-targeted therapy in the treatment of renal cell carcinoma (RCC). Methods: Nude/beige mice bearing human RCC xenografts were treated with various combinations of sunitinib and the HDM2 antagonist MI-319. Tumors were excised at various time points before and during treatment and analyzed by western blot and IHC for evidence of p53 activation and function. Results: Sunitinib treatment increased p53 levels in RCC xenografts and transiently induced the expression of p21waf1, Noxa, and HDM2, the levels of which subsequently declined to baseline (or undetectable) with the emergence of sunitinib resistance. The development of resistance and the suppression of p53-dependent gene expression temporally correlated with the induction of the p53 antagonist HDMX. The concurrent administration of MI-319 markedly increased the antitumor and anti-angiogenic activities of sunitinib and led to sustained p53-dependent gene expression. It also suppressed the expression of the chemokine SDF-1 (CXCL12) and the influx of CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSC) otherwise induced by sunitinib. Although p53 knockdown markedly reduced the production of the angiostatic peptide endostatin, the production of endostatin was not augmented by MI-319 treatment. Conclusions: The evasion of p53 function (possibly through the expression of HDMX) is an essential element in the development of resistance to VEGF-targeted therapy in RCC. The maintenance of p53 function through the concurrent administration of an HDM2 antagonist is an effective means of delaying or preventing the development of resistance.
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    Resistance of Renal Cell Carcinoma to Sorafenib Is Mediated by Potentially Reversible Gene Expression
    (Public Library of Science, 2011) Bhasin, Manoj; Schor-Bardach, Rachel; Collins, Michael P.; Zhang, Liang; Wang, Xiaoen; Panka, David; Putheti, P; Signoretti, Sabina; Alsop, David; Libermann, Towia; Atkins, Michael B.; Mier, James; Goldberg, S.; Bhatt, Rupal
    Purpose: Resistance to antiangiogenic therapy is an important clinical problem. We examined whether resistance occurs at least in part via reversible, physiologic changes in the tumor, or results solely from stable genetic changes in resistant tumor cells. Experimental Design: Mice bearing two human RCC xenografts were treated with sorafenib until they acquired resistance. Resistant 786-O cells were harvested and reimplanted into naïve mice. Mice bearing resistant A498 cells were subjected to a 1 week treatment break. Sorafenib was then again administered to both sets of mice. Tumor growth patterns, gene expression, viability, blood vessel density, and perfusion were serially assessed in treated vs control mice. Results: Despite prior resistance, reimplanted 786-O tumors maintained their ability to stabilize on sorafenib in sequential reimplantation steps. A transcriptome profile of the tumors revealed that the gene expression profile of tumors upon reimplantation reapproximated that of the untreated tumors and was distinct from tumors exhibiting resistance to sorafenib. In A498 tumors, revascularization was noted with resistance and cessation of sorafenib therapy and tumor perfusion was reduced and tumor cell necrosis enhanced with re-exposure to sorafenib. Conclusions: In two RCC cell lines, resistance to sorafenib appears to be reversible. These results support the hypothesis that resistance to VEGF pathway therapy is not solely the result of a permanent genetic change in the tumor or selection of resistant clones, but rather is due to a great extent to reversible changes that likely occur in the tumor and/or its microenvironment.