BC Cancer Foundation

Transmembrane Protease, Serine-2 (TMPRSS2) and TMPRSS11D are human proteases that enable SARS-CoV-2 and Influenza A/B virus infections, but their biochemical mechanisms for facilitating viral cell entry remain unclear. We show these proteases spontaneously and efficiently cleave their own zymogen activation motifs, activating their broader protease activity on cellular substrates. We determine TMPRSS11D co-crystal structures with a native and an engineered activation motif, revealing insights into its autocleavage activation and distinct substrate binding cleft features. Leveraging this structural data, we develop nanomolar potency peptidomimetic inhibitors of TMPRSS11D and TMPRSS2. We show that a broad serine protease inhibitor that underwent clinical trials for TMPRSS2-targeted COVID-19 therapy, nafamostat mesylate, was rapidly cleaved by TMPRSS11D and converted to low activity derivatives. In this work, we develop mechanistic insights into human protease viral tropism and highlight both the strengths and limitations of existing human serine protease inhibitors, informing future drug discovery efforts targeting these proteases.

BackgroundGiven how crucial molecular-biomarker testing is to treatment decisions for advanced non-small cell lung cancer (NSCLC), guidelines recommend a turnaround time (TAT) of 14 calendar days from receiving specimen to test result, and 3 days to receive a specimen from outside pathology lab. Current TAT for molecular-biomarker testing in British Columbia (BC), Canada frequently exceeds these recommendations. Thus, we launched a quality improvement (QI) initiative to improve TAT of molecular-biomarker testing.MethodsWe assembled a multidisciplinary team to identify areas contributing to delays in molecular-biomarker testing. We designed and conducted three Plan-Do-Study-Act (PDSA) cycles. Cycles 1 and 2 involved changing requisition delivery method from fax to email between BC Cancer Vancouver Centre (BCCV) and two outside hospitals with the highest volume of specimens. Cycle 3 introduced parallel processing of specimens at BCCV pathology lab and concurrent molecular-biomarker testing. TAT was evaluated before and after these process changes along with staff satisfaction via survey.ResultsThe average TAT from test request to specimen received by BCCV was reduced from 6.4 days prechange to 4.6 days postchange. The TAT from specimen receipt by BCCV to report availability was reduced from a median of 22–16 days. Report availability for initial medical oncology consultation increased from a median of 13%–29%. The staff satisfaction survey revealed an enhanced experience with the new process, particularly for our nurse navigator.ConclusionThe TAT for molecular-biomarker testing is an ongoing and complex challenge for healthcare systems worldwide. This QI project is a step towards addressing province-wide reduction in wait times for molecular-biomarker testing results in BC. We continue to explore further ideas to improve workflow metrics and patient care among patients with advanced NSCLC.

BackgroundPrimary cardiac sarcoma (PCS) is a rare but often fatal disease. The current study aimed to analyze the impact of baseline demographics, local and systemic therapies in a contemporary cohort.MethodsClinical records of PCS across six institutions in three continents were reviewed. Kaplan‐Meier method was used to estimate survival. Cox proportional hazard model was used to determine variables impacting progression‐free survival (PFS) or overall survival (OS).ResultsSixty‐one patients with PCS (1996‐2016) were identified. The median age at diagnosis was 46 (range 18‐79); 36% (n = 22) presented with metastatic disease. The most common histology was angiosarcoma (n = 24, 39%). A total of 46 patients received surgery (75%) but only 5 (8%) patients achieved R0 resection. Multi‐modality treatment to the primary tumor was given to 28 patients (46%; localized disease 23/39 (59%); metastatic disease 5/22 (23%)). The median OS for the entire cohort was 17.5 months (95% CI 9.5‐20.6), with seven (11%) patients surviving longer than 36 months. On multi‐variate analysis, age <65 (P = 0.01) was the only significant favorable prognostic factor. For first‐line palliative chemotherapy, the median PFS was 4.4 months (95% CI 2.9‐7.7 months). The best response for first‐line chemotherapy was 32% (CR = 1, PR = 9). No significant improvement in OS was identified in patients presenting throughout the 20‐year period of this review.ConclusionYounger age at diagnosis was associated with improved outcome although the prognosis of PCS remains poor. Given the lack of improvement in survival, further dedicated research is required.

TPS11136 Background: Lung cancer is the most common cause of cancer-related deaths in North America. A number of pharmaceutical firms currently have therapies that target ALK-driven lung cancers in development, with the first-in-class FDA-approved ALK inhibitor Xalkori (crizotinib, Pfizer) demonstrating excellent anti-tumor responses without significant toxicities. There is now substantial interest in ensuring the accurate identification of those NSCLC patients who harbor ALK fusions. The ALK qPCR assay is a quantitative real-time PCR assay that offers high throughput, 24-48 hour TAT, and easily interpretable results. We are performing a clinical diagnostic trial, PCRTALK (PCR tumor ALK), with the primary objective of this trial being to unequivocally demonstrate the performance of the ALK qPCR assayagainst current ALK testing modalities in screening FFPE lung cancer biopsy specimens. The study is recruiting multiple clinical centers throughout Canada for patient enrollment. Once PCRTALK has been completed, our goal is to accomplish the following: (1) the trial will provide clinically relevant data on which types of lung cancer biopsies (bronchoscopy, FNA, CNB, pleural fluid thoracentesis) provide sufficient tissue for the different modalities of ALK testing and report on the number of cases rejected for ALK testing by IHC and FISH due to insufficient tissue; and (2) provide therapeutic outcome data for cases with discordant ALK diagnostic results. A second arm of the study is to conduct a correlative study analyzing both matched FFPE and blood collected from NSCLC patients using various non-invasive methodologies. Methods: The study will proceed according to the following work flow: (1) ALK IHC (ALK IHC-5A4, Leica Biosystems) conducted by BCCA laboratories; (2) 72 individual ALK IHC 5A4-positives and 72 ALK IHC 5A4-negatives selected according to their respective IHC scores and reflexed to 3 - 5; (3) ALK FISH (Abbott Diagnostics) performed on all 144 specimens; (4) The ALK qPCR assay performed on all 144 specimens; and (5) Sanger and/or NGS to determine true status. Initial PCRTALK clinical trial data will be presented together with conclusions based on the results. Clinical trial information: NCT02010047.