Pancreatic and hepatocellular cancers have poor survival rates. Based on data from the prior funding cycle showing that the multi-kinase inhibitor sorafenib synergistically interacts with the histone deacetylase inhibitor (HDACI) vorinostat to activate CD95 and kill renal, hepatocellular and pancreatic cancer lines, Bayer and Merck have sponsored phase I trials that will start in 2009. We also have published data demonstrating that geldanamycins (17AAG, 17DMAG) + MEK1/2 inhibitors synergize to kill liver and pancreatic tumor cells via CD95 activation. Both drug combinations cause a novel form of CD95 activation which is obligate for cell killing, but whether these combinations utilize all of the same molecular mechanisms to activate CD95 is unknown. We hypothesize based on published and preliminary data that Ca2+-dependent ROS generation by combined HSP90 antagonist and MEK1/2 inhibitor exposure will represent a key signal for ceramide- dependent CD95 activation and cell killing. We hypothesize, based on published and preliminary data, that inhibition of the class III RTK, PDGFRb, will represent a key primary target for sorafenib in the regulation of CD95 toxicity and autophagy regulation. We hypothesize that HDACIs potentiate sorafenib toxicity, in part, because they increase as a secondary event expression of CD95 and/or FAS-L via NFkB activation. Thus:
Specific Aim 1 : To determine the molecular mechanisms by which geldanamycin + MEK1/2 inhibitor treatment activates CD95.
Specific Aim 2 : To determine the molecular mechanisms by which sorafenib and vorinostat treatment activates CD95.
Specific Aim 3 : To determine mechanistically the relative importance of promoting additional extrinsic or intrinsic pathway activation to enhance the lethality of sorafenib+vorinostat in vitro and in vivo. Our goal is to determine in precise molecular detail the mechanisms of action of these drug combinations upstream of CD95 to improve their future clinical application, and to progress our yet-to-be translated findings from the bench / vivarium, to the bedside.

Public Health Relevance

. Pancreatic cancer is diagnosed in ~ 37,000 patients per annum, with ~34,000 deaths and a 5 year survival rate of <5%. Hepatoma is diagnosed in ~19,000 patients per annum with ~17,000 deaths, with a 5 year survival of <10%. Thus, pancreatic and hepatocellular cancers have very poor survival rates. Based on our published data from the prior cycle of funding, combining the multi-kinase inhibitor sorafenib with the histone deacetylase inhibitor (HDACI) vorinostat that demonstrated synergistic toxicity effects in Renal CC, HCC and pancreatic lines, Bayer and Merck have sponsored phase I trials in RCC and HCC that will start during 2009. Our goal now is to determine in even greater detail the mechanisms of action of these drugs to improve their future clinical application e.g. rationally, combined with additional targeted agent(s). In parallel studies, we published that geldanamycins and MEK1/2 inhibitors also demonstrate synergistic toxicity effects in Renal CC, HCC and pancreatic lines. Thus the secondary goal of this proposal is to prove detailed mechanistic mode-of-action data to move geldanamycin+MEK1/2 inhibitor therapy from the bench / vivarium, to the bedside.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052825-15
Application #
8477173
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Serrano, Jose
Project Start
1999-05-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
15
Fiscal Year
2013
Total Cost
$276,784
Indirect Cost
$91,644
Name
Virginia Commonwealth University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Tavallai, Mehrad; Booth, Laurence; Roberts, Jane L et al. (2016) Ruxolitinib synergizes with DMF to kill via BIM+BAD-induced mitochondrial dysfunction and via reduced SOD2/TRX expression and ROS. Oncotarget 7:17290-300
Booth, Laurence; Roberts, Jane L; Tavallai, Mehrad et al. (2016) The afatinib resistance of in vivo generated H1975 lung cancer cell clones is mediated by SRC/ERBB3/c-KIT/c-MET compensatory survival signaling. Oncotarget 7:19620-30
Booth, Laurence; Albers, Thomas; Roberts, Jane L et al. (2016) Multi-kinase inhibitors interact with sildenafil and ERBB1/2/4 inhibitors to kill tumor cells in vitro and in vivo. Oncotarget 7:40398-40417
Booth, Laurence; Roberts, Jane L; Tavallai, Mehrad et al. (2015) OSU-03012 and Viagra Treatment Inhibits the Activity of Multiple Chaperone Proteins and Disrupts the Blood-Brain Barrier: Implications for Anti-Cancer Therapies. J Cell Physiol 230:1982-98
Booth, Laurence; Roberts, Jane L; Cruickshanks, Nichola et al. (2015) PDE5 inhibitors enhance celecoxib killing in multiple tumor types. J Cell Physiol 230:1115-27
Webb, Timothy; Carter, Jori; Roberts, Jane L et al. (2015) Celecoxib enhances [sorafenib + sildenafil] lethality in cancer cells and reverts platinum chemotherapy resistance. Cancer Biol Ther 16:1660-70
Goodson 3rd, William H; Lowe, Leroy; Carpenter, David O et al. (2015) Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead. Carcinogenesis 36 Suppl 1:S254-96
Tavallai, Mehrad; Hamed, Hossein A; Roberts, Jane L et al. (2015) Nexavar/Stivarga and viagra interact to kill tumor cells. J Cell Physiol 230:2281-98
Roberts, Jane L; Tavallai, Mehrad; Nourbakhsh, Aida et al. (2015) GRP78/Dna K Is a Target for Nexavar/Stivarga/Votrient in the Treatment of Human Malignancies, Viral Infections and Bacterial Diseases. J Cell Physiol 230:2552-78
Hamed, Hossein A; Tavallai, Seyedmehrad; Grant, Steven et al. (2015) Sorafenib/regorafenib and lapatinib interact to kill CNS tumor cells. J Cell Physiol 230:131-9

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