To begin, Dr. Lerner emphasized that the current, “one size fits all” approach is inefficient and may deprive some patients of life-saving therapy. He highlighted the case of a patient of his who presented with metastatic bladder cancer and was started on dose-dense MVAC but rapidly progressed and died within weeks of the diagnosis of metastatic disease. Biopsy of a metastatic site facilitated testing using the Tempus panel which identified actionable and targetable mutations, however, this patient was unable to receive such therapy.
He then highlighted the rationale for the integration of systemic and surgical therapy for muscle-invasive bladder cancer. Despite level 1 evidence for the use of cisplatin-based neoadjuvant chemotherapy, pathologic response rates are 50% and the absolute overall survival benefit is less than 10%. Thus, there remains a huge unmet need with many patients ineligible for this therapy (~50%) and nearly half of those who are eligible not responding, leaving nearly 75% of patients without benefit from level 1 supported approaches.
Drawing on data from Grossman and colleagues, Dr. Lerner emphasized that patients who have residual muscle-invasive disease following neoadjuvant chemotherapy do poorly and there is no standard of care for these individuals.
As alternatives to cytotoxic chemotherapy, approaches including immunotherapy combined chemoimmunotherapy and targeted therapy (using tyrosine kinase inhibitors) may offer promise. Mutations in pathways that can be targeted using these inhibitors are relatively common (71-89%) thus increasing the potential number of patients who may benefit from systemic therapy.
Identifying patients who are unlikely to benefit from the current standard of care chemotherapy is therefore important if we can offer them an alternative that may be more effective. There is evidence that resistance pathways may be characterized on the basis of wound repair pathways (that may be targetable with celecoxib) and well as a cisplatin-resistance signature and an atezolizumab resistance signature (TGF-beta).
Integrating these, Dr. Lerner hypothesized that integrated analysis of proteomics and genomic of muscle-invasive bladder cancer can allow for the identification of mechanisms of chemotherapy resistance and lead to specific targeted therapies in those who are resistant to our current standard of care approaches. To assess this, the biobanking workflow involves initial restaging TURBT at which time tumor tissue and other biologic samples can be collected. Subsequently, patients receive chemotherapy followed by repeat resection with the collection of each of these specimens prior to definitive therapy.
In unpublished data, Dr. Lerner highlighted an interaction between the 5 TCGA bladder cancer sub-types and chemotherapy sensitivity with supervised clustering identifying differential protein expression among the resistant and sensitive tumors. A number of specific protein targets appear to be involved in the process of chemotherapy resistance in this approach.
Dr. Lerner then discussed work from Dr. Kim and Dr. Ellis in which multiplexed inhibitor bead Kinome Pull-down profiling utilizing a mixture of 9 kinase inhibitors is used to isolate and enrich for kinases with the most activity. This approach stratifies by chemotherapy sensitivity with a number of potentially actionable targets. For example, ATR is an identified target which has recently be assessed in a phase I trial of M6620 (VX-970), an ATR inhibitor, either alone or in combination in patients with advanced solid tumors.
Dr. Lerner then transitioned to discussing the chorioallantoic membrane (CAM) patient-derived xenograft model, which he suggested could serve as a high-throughput model. This model allows approximately a 7-10 day window for assessment before immune infiltration results in death of the embryo. Notably, approximately 2/3 attempts successfully engrafted with this model. The goal of this approach is to apply information from proteomic assessment into xenograft models to test treatment alternatives.
In conclusion, Dr. Lerner highlighted the opportunity for “big data” at the NCI, to integrate imaging, genomics and proteomics to improve prevention, diagnosis, and treatment. This approach is utilized in the CPTAC pipeline.
Bladder cancer is one of the tumor sites of interest in V04.02 of CPTAC across a number of disease states.
Presenter: Seth Lerner, MD, FACS, Professor Urology, Beth and Dave Swalm Chair in Urologic Oncology, Director of Urologic Oncology, and Director of the Multidisciplinary Bladder Cancer Program, Baylor College of Medicine, Houston, TX US
Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center, Contact: @WallisCJD on Twitter at the 2020 Société Internationale d'Urologie Virtual Congress (#SIU2020), October 10th - October 11th, 2020