Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease in urgent need of newer molecularly targeted drugs. Aberrations in the Kras oncogene for long have been appreciated to be a major driver of this disease. Ras genes code for a set of proteins that are instrumental in cellular signaling, and when mutated, permit uncontrolled cellular proliferation in PDAC. Even though, the Ras signaling network has been well understood, however this knowledge could not be translated into developing new cancer drugs. This is primarily because Ras proteins lack the ideal binding pockets that usually serve as attractive targets for small molecule drugs. To overcome this scientific challenge, newer targets, either from the Ras structure itself, or from critical direct interacting partners or downstream effectors of Kras (here the p21 activated kinase 4/PAK4) need to be urgently exploited. The PAK family members are key effectors downstream of Ras, which act as regulatory switches that control critical cellular processes, leading to tumor aggressiveness. Recently, studies have shown amplification of PAK4 gene in large PDAC patient cohorts. Our investigations in gemcitabine (GEM) resistant PDAC models showed a very strong correlation between PAK4 over-expression and drug resistance. Therefore we hypothesize that PAK4 protein is an attractive druggable candidate in the elusive Ras pathway and its inhibition will overcome GEM resistance by suppressing Kras mediated proliferative signaling in PDAC. Earlier unsuccessful attempts to target PAK4 (tested in non-pancreatic models) resulted in the development of a Type I ATP competitive inhibitor PF-03798309 that was prematurely discontinued based on a single clinical trial in view of its undesirable pharmacokinetic characteristics due to excessive drug efflux through multi-drug resistance proteins (MDRs). Since then there have been no serious attempts to develop newer and superior inhibitors against this elusive protein, and thus there is a void in our knowledge in relation to PAK4 inhibitors. Filling this scientific void we have developed the first in class Type II allosteric modulators of PAK4 that show selective activity in resistant pancreatic cancer. Most importantly, unlike PF-03798309, our Type II PAK4 allosteric modulators are not substrates to multi-drug resistance (MDR) proteins. In this highly translational proposal, the utility of our novel PAK4 inhibitors against resistant PDAC will be delineated. These studies will help in the understanding of PAK4 dependent resistance mechanisms in PDAC.
Our specific aims are:
Aim -1: Demonstrate that PAK4 is a diagnostic and therapeutic biomarker for resistant PDAC.
Aim -2: Evaluate the impact on tumor growth of PAK4 inhibition in orthotopic and well recognized pancreatic cancer transgenic [KrasG12D/+; LSL-Trp53 R172H/+; Pdx-1-Cre] animal models. Impact: Our newly discovered Type II PAK4 allosteric modulators show activity against therapy resistant PDAC. The outcome of our proposed pre-clinical studies will enable us to have a focused design, toxicity and efficacy testing of PAK4 allosteric modulators in PDAC.
Oncogenic Ras (Kras) has been well document to be the major aberration (>75% mutations) driving the therapy resistant and deadly Pancreatic Ductal Adenocarcinoma (PDAC); a disease in urgent need of newer therapeutic modalities. Nevertheless, the last three decades have not seen any success in the development of Kras targeted therapeutics primarily because, unlike other druggable proteins, Ras lacks the ideal cavities that usually serve as attractive targets for small molecule drugs. To overcome the scientific challenge, newer druggable avenues either through the Ras structure itself or via critical downstream effectors of Ras must be urgently discovered. Filling this scientific void, in collaboration with Karyopharm Therapeutics, we have developed first in class Type II allosteric modulators against Ras downstream effector p21 activated kinase (PAK4) that show selective activity against PDAC. The proposed studies will evaluate the impact of PAK4 inhibition in therapy resistant PDAC cell and animal models. These studies will translate into future clinical trials bringing PAK4 as a new form of therapy against deadly and by far incurable PDAC.
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