Project I: Targeting ubiquitination machinery to destabilize oncoprotein stability. Accumulation of oncogene-specific activating mutations undoubtedly plays a key role not only in cancer initiation and progression, but in many instances further promotes drug resistance. Mutation, which alters the primary amino acid sequence in an oncogene, changes its function and protein-protein interaction abilities mediated via altered protein folding and stability. In our laboratory we focus on studying the activating mutations of two critical oncogenes: epidermal growth factor receptor (EGFR) and mutant KRAS. Recently, we have obtained data that a HECT type ubiquitin ligase (E3), SMad Ubiquitination Regulatory Factor 2 (SMURF2) enhances protein stability of mutant KRAS. In contrast, loss or catalytic inactivation of SMURF2 causes rapid mutant KRAS degradation to kill such oncogene-addicted cancer cells. Our long-term objective is to develop a novel therapeutic strategy to target mutant KRAS to enhance tumor specific chemo- and radio-sensitization via SMURF2 targeting. Our approach has two novel aspects: (a) Basic aspect: Improving our current molecular understanding how SMURF2 cooperates with mutant KRAS to promote oncogenesis. Towards that we are employing a genetic approach using conditional knockout and transgenic mouse models to establish the role of SMURF2-KRAS signaling axis in lung and pancreatic cancer; and (b) Translational aspect: We are exploring the therapeutic potential of novel small molecules to degrade mutant KRAS protein via disruption of protein-protein interactions.
In collaborations with the David Beer lab, we are also utilizing our ubiquitination expertise to decipher the role of a RING-type ubiquitin ligase, RNF128/Grail in the maintenance of mutant TP53 protein stability essential for Barrett’s progression to low grade (LGD) to high grade (HGD) to esophageal adenocarcinoma (EAC).
Project II: Lung radioprotection by inhibition of TNF-α signaling. The efficacy of radiation therapy for upper thoracic cancers is limited by radiation-induced lung toxicity (RILT). Amifostine, a radical scavenger and the only FDA-approved radioprotector does not protect the lung and has its own substantial toxicity. Thus, there is an absolute need to develop a lung radioprotector for which we need to improve our understanding of the molecular regulators involved in RILT. Among different mediators, release of inflammatory cytokines has been well documented. Among them, early release of tumor necrosis factor-alpha (TNF-a) is reported to play a critical role in the initiation of inflammatory responses. We have shown that blocking TNF-a signaling either via genetic knockdown or via antisense oligonucleotide silencing of the TNF receptor I, can protect mouse lung from radiation injury without altering tumor cell killing, and thus may provide therapeutic selectivity. Additionally, inhibition of TNF-a by neutralizing antibody, Etanercept (Enbrel), improves lung function for patients with idiopathic pulmonary syndrome, which results from lung injury after high dose chemotherapy. The long-term goal of our study is to better understand the molecular regulators involved in RILT and further develop improved agents that can provide lung protection during radiotherapy without compromising radio-/chemotherapy induced tumor cell killing. Tristetraprolin (TTP), a RNA-binding anti-inflammatory protein, is known to negatively regulate TNF-a production by degrading cytokine transcript in various systems including RILT. Our study further identified p38 MAPK activation upon radiation as a key step essential for phosphorylation-mediated functional inactivation of TTP that allows increased TNF-a production. Thus, we hypothesized and currently testing the effect of various p38 kinase inhibitors as a probable lung radioprotector using animal models. Our long-term goal is to test the potential of a p38 inhibitor as a novel lung protector in the clinic.