Curtis R. Pickering, PhD

The Pickering lab approach to translational genomics is to start with interesting genomic findings, understand the biology of those findings, and then identify approaches to translate them to improved patient care. Below are examples of recent or ongoing projects in the lab

Sensitizing HNSCC to necroptosis

Caspase 8 (CASP8) mutations are found in about 10% of all HNSCC and 15% of tumors in the oral cavity subsite. CASP8 mutant tumors have increased HRAS mutations, a quiet copy number profile, and increased expression of cytolytic immune genes. These and other markers suggested that CASP8 mutations are relevant to HNSCC biology and should be investigated further. CASP8 sits at the nexus of extrinsic apoptotic death and necroptosis. CASP8 stimulates apoptosis while inhibiting necroptosis. We found that inhibition of CASP8 function can promote a nectoptotic death in HNSCC models with functional RIP3. Adding an IAP inhibitor to radiotherapy enhances the treatment response, particularly in tumors with reduced CASP8 function. The IAP inhibitor xevinapant is currently in clinical trials in HNSCC in combination with chemoradiotherapy and theses studies could identify if CASP8 mutation status or other alterations sensitize to IAP inhibition in patients. (PMID: 33108350)

Oncogenic CREBBP/EP300 mutations alter DNA repair

Mutations to the acetyltransferases CREBBP and EP300 are found in about 17% of HNSCC and are associated with worse outcomes in radiation treated patients. In an in vivo shRNA library screen for radiosensitizers, we found that knock-down of CREBBP/EP300 sensitized to radiation in cell lines with mutations in CREBBP/EP300. Mechanistically, some of the CREBBP/EP300 mutations function as activating mutations and increase histone and protein acetylation. They also increase homologous recombination DNA repair functions. Inhibition of CREBBP/EP300 with shRNA or the small molecule A485 can sensitize to radiation in CREBBP/EP300 mutant models. This project has identified new biology of the genes CREBBP/EP300 and a potential therapeutic approach to radiosensitize tumors with specific genomic alterations. This work is in collaboration with the Skinner lab at UPMC. (PMID: 34732714)

Improving biomarkers for oral leukoplakia

Oral leukoplakia is a common type of plaque in the oral cavity that indicates an increased risk of oral cancer. Oral leukoplakia is identified by a visual inspection and diagnosed by a combination of clinical and histological features. Many leukoplakia exhibit dysplasia that can be graded as mild, moderate, or severe by an oral pathologist. However, the grading is highly variable between pathologists, so the prognostic power is low. The only treatments for oral leukoplakia are laser ablation and surgical removal. Since these lesions can cover large areas of the oral cavity and persist for many years without progression to cancer, they are usually not treated until they progress to severe dysplasia or cancer. Improved prognostic biomarkers are needed for this disease. We have found that machine learning tools can be used on H&E stained histologic images of oral leukoplakia to identify the patients at highest risk of progression to oral cancer. It should be possible to further improve these models with the addition of genomic and immune markers. Together, these tools should be able to improve our ability to identify both low and high-risk oral leukoplakia. This could reduce the morbidity of frequent biopsies for patients with low-risk leukoplakia and more quickly identify useful therapeutics for high-risk leukoplakia. This work is in collaboration with the Xiao lab at UTSW.