J. Joshua Smith: Research Overview

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The J. Joshua Smith Laboratory focuses on making better models of rectal cancer (RC). My laboratory group developed the first patient-derived rectal cancer organoids. These rectal cancer organoids recapitulate the clinical and molecular features of patients with rectal cancer and uniquely reflect the clinical responses to therapy of the patients from which they were derived. I obtained an R37 grant from the National Institutes of Health to further develop and expand this rectal cancer model, and my work as a clinician and clinical trialist completely overlaps with my basic and translational work.  Our focus is on improving response to neoadjuvant therapies for patients with rectal cancer by developing better disease models. I have a strong collaborative relationship with surgeon Julio Garcia-Aguilar, Chief of the Colorectal Service; radiation oncologist Paul Romesser; and surgeon Philip Paty, and through this unique collaborative initiative, we have been able to identify novel radiosensitizers to take forward into phase 1 clinical trials with parallel co-clinical trials in patient-derived organoids. Further, we have improved our initial in vivo endoluminal rectal cancer model by translating it to the immunocompetent setting to better understand the biology contributing to chemoresistance and radioresistance in rectal cancer.

I am actively working to extend and validate findings from the OPRA (organ preservation of rectal adenocarcinoma) trial (https://pubmed.ncbi.nlm.nih.gov/35483010/) to better identify complete responders to neoadjuvant therapy (NAT) with the end goal of increasing the number of patients who can benefit from organ preservation. Our RC tumoroid model fills an unmet need by enabling the discovery of robust, cost-effective molecular biomarkers for RC patients. To translate our preclinical results, there is a critical need to develop reproducible, robust, and clinically useful biomarker panels for identifying RC patients most likely to benefit from NAT. Furthermore, it is imperative to discover new biomarkers for targeted treatments in patients that are resistant to chemotherapy and/or chemoradiation as some modern trials have explored a chemotherapy-first approach versus chemoradiation followed by chemotherapy.

We are uniquely positioned to address these needs and identify reliable biomarkers as we can derive pretreatment patient-specific models and iterative models at separate points during treatment to isolate the effects of chemotherapy and other components of NAT (e.g., chemoradiation). Tumoroids consist of tumor epithelial cells and we have shown that our RC tumoroid model corresponds to chemotherapy response of RC patients.  Therefore, the premise of an upcoming multiple principal investigator (multi-PI) RO1 application with longtime collaborator Dr. Xi Chen of the University of Miami is to maximize the utility of our model to identify effective intrinsic molecular biomarkers for NAT response by strategically combining genomic data using novel machine learning approaches from tumoroids and matched primary tumors of RC patients. Lastly, as an active clinical trialist, in collaboration with Dr. Romesser, and as the Chair of a national phase 2 trial (the Janus rectal cancer trial) that builds on the findings from Dr. Garcia-Aguilar’s OPRA trial, I am well positioned to ask and answer relevant translational and clinical research questions to improve outcomes for rectal cancer patients.