Not all mutant KRas proteins affect patient survival or downstream signaling in a similar way. The heterogeneous behavior of mutant KRas proteins implies that therapeutic interventions may need to take into account the specific mutant KRas expressed by the tumor.

Pancreatic cancer is characterized by a desmoplastic reaction that creates a dense fibroinflammatory microenvironment, promoting hypoxia and limiting cancer drug delivery due to decreased blood perfusion. Here we describe a novel tumor-stroma interaction that may help explain the prevalence of desmoplasia in this cancer. Specifically, we found that activation of HIF-1α by tumor hypoxia strongly activates secretion of the sonic hedgehog ligand SHH by cancer cells which in turn causes stromal fibroblasts to increase fibrous tissue deposition. In support of this finding, elevated levels of HIF-1α and SHH in pancreatic tumors were determined to be markers of decreased patient survival. Repeated cycles of hypoxia and desmoplasia amplified each other in a feed forward loop that made tumors more aggressive and resistant to therapy. This loop could be blocked by HIF-1α inhibition, which was sufficient to block SHH production and HH signaling. Taken together, our findings suggest that increased HIF-1α produced by hypoxic tumors triggers the desmoplasic reaction in pancreatic cancer, which is then amplified by a feed forward loop involving cycles of decreased blood flow and increased hypoxia. our findings strengthen the rationale for testing HIF inhibitors may therefore represent a novel therapeutic option for pancreatic cancer.

Over the long term, LRYGB had an approximate reduction of 15 kg/m(2) BMI and 60% EWL, a significantly better outcome than LAGB patients experienced with band intact. The main issue with LAGB was its 50% failure rate in the long term, as defined by poor weight loss and percentage of band removal. Nevertheless, LAGB had a remarkably safe course, and it may therefore be considered for motivated and informed patients.

Clear cell kidney cancer (CRCC) is initiated typically by loss of the tumor suppressor VHL, driving constitutive activation of HIF-1 and HIF-2. However, whereas HIF-1 has a tumor suppressor role, HIF-2 plays a distinct role in driving CRCC. In this study, we show that the HIF-1α E3 ligase HAF complexes with HIF-2α at DNA to promote HIF-2-dependent transcription through a mechanism relying upon HAF SUMOylation. HAF SUMOylation was induced by hypoxia, whereas HAF-mediated HIF-1α degradation was SUMOylation independent. HAF overexpression in mice increased CRCC growth and metastasis. Clinically, HAF overexpression was associated with poor prognosis. Taken together, our results show that HAF is a specific mediator of HIF-2 activation that is critical for CRCC development and morbidity.

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<div>Abstract<p>Clear-cell renal cell cancer (CRCC) is initiated typically by loss of the tumor-suppressor VHL, driving constitutive activation of hypoxia-inducible factor-1 (HIF1) and HIF2. However, whereas HIF1 has a tumor-suppressor role, HIF2 plays a distinct role in driving CRCC. In this study, we show that the HIF1α E3 ligase hypoxia-associated factor (HAF) complexes with HIF2α at DNA to promote HIF2-dependent transcription through a mechanism relying upon HAF SUMOylation. HAF SUMOylation was induced by hypoxia, whereas HAF-mediated HIF1α degradation was SUMOylation independent. HAF overexpression in mice increased CRCC growth and metastasis. Clinically, HAF overexpression was associated with poor prognosis. Taken together, our results show that HAF is a specific mediator of HIF2 activation that is critical for CRCC development and morbidity. <i>Cancer Res; 75(2); 316–29. ©2014 AACR.</i></p></div>

Epicutaneous (topical) therapy with molecularly targeted agents is an attractive modality for treatment of basal cell carcinoma (BCC), early UVB induced squamous cell carcinoma (SCC) and cutaneous metastatic disease (CMD) associated with metastatic breast cancer. There is evidence that Akt and PDKP1 play complimentary yet independent roles in PI3K pathway signaling associated with driving the growth of BCC, UVB induced SCC, and breast CMD. Both Akt and PDPK1 possess a pleckstrin homology (PH) domain, a highly conserved three-dimensional superfold with a high affinity for binding phosphatidylinositol-3-phosphates, causing Akt and PDPK1 to translocation to the plasma membrane where Akt is activated. Through reiterative molecular docking and structure refinement using a proprietary computational platform, we have identified PHT-427 as an agent that binds to the PH domains of Akt and PDPK1, inhibiting their activity. PHT-427 has antitumor activity when administered orally but importantly also following epicutaneous administration. We evaluated the antitumor potential of epicutaneous PHT-427 against CMD in an intradermal breast xenograft model and in an early UVB induced skin cancer model in mice. For the CMD investigation MCF-7 human breast cancer (mutant PIK3CA) was injected intradermally in the flank of female nu/nu mice. Groups of 5 mice were treated twice a day for 10 days with vehicle or 0.1ml PH-427 (50 mg/mL) applied to a 1 cm patch of skin over the tumor. The mice were euthanized 4 hr after the last application and blood, tumor and overlying skin were removed for analyzes. Topical PHT-427 produced 89% inhibition of tumor growth (3/5 no measurable tumor) with no change in body weight or skin toxicity and inhibited targets in skin and tumor. Levels of PHT-427 by HPL-MS were detected in the skin at the site of application, in tumor and in plasma. To evaluate the activity PHT-427 in early UVB induced skin cancer female SKH-1 hairless mice were exposed to UVB irradiation to induce Akt and the production of skin tumors. The mice were treated epicutaneously with PHT-427 or vehicle 3 times a week for 4 weeks at which point animals were sacrificed and skin, tumors and blood were obtained. In this study topical PHT-427 significantly reduced tumor incidence, tumor burden and tumor multiplicity. Following treatment with PHT-427 80% of mice were tumor free and those with tumors averaged fewer than 1 per mouse and those were &lt; 1mm in size while 59% of untreated group had tumors, with 1.6 tumors per mouse and the majority &gt; 1mm in size. There was no change in body weight and no apparent skin toxicity. Thus, topical application of PHT-427 can deliver active drug to skin and tumor, inhibiting AKT and PDPK1, both of which drive the PI3K pathway important in UVB induced SCC and breast CMD, with significant inhibition of tumor growth without adverse effects on normal skin. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A213.

<p>Supplementary Figure Legends - PDF file 90K, Figure legends for Supplementary Material</p>