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Implementation of an Interdisciplinary Precision Oncology Program at the Madison VA
Background
The William S. Middleton Memorial Veterans Hospital (Madison VA) prioritized the goal of ensuring patients with cancer are receiving guideline-based precision oncology care, including comprehensive genomic profiling (CGP) and germline genomics consultation based on evidence-based medicine and the VA Clinical Pathways. A local Precision Oncology Program was created to assist in review of CGP results including documentation in the electronic medical record (EMR) and recommendations for treatment or additional testing as appropriate. The program, which began in February 2024, focused on patients with prostate cancer initially. This was expanded to all genitourinary cancers in April 2024, non-small cell lung cancers (NSCLC) in August 2024, and all cancers in Dec 2024.
Results
Since the implementation of the Madison VA Precision Oncology Program, CGP was reviewed for 73 unique Veterans leading to 281 recommendations including: 25 FDA approved therapies, 2 off-label standard of care treatment options, 11 patients with potential clinical trial eligibility at the Madison VA. Forty-eight patients had no actionable mutations and 44 were recommended for additional germline genetics counseling. For patients with metastatic prostate cancer, after 1 year of program implementation, an increase was seen in the percentage of patients receiving guideline-based CGP, the percentage of actionable alterations identified, and the percentage of patients identified as potentially eligible for a clinical trial open at the Madison VA based on CGP. The percentage of patients with an interfacility consult to the Clinical Cancer Genetics Service was also increased. For patients with metastatic NSCLC, after 6 months of program implementation, an increase was seen in the percentage of patients appropriately receiving CGP, the percentage of actionable alterations identified, and the percentage of patients on targeted therapy. In all cases where an actionable alteration was not being targeted, the treatment option was not yet appropriate for the stage of disease.
Conclusions
The implementation of preemptive review of all CGP results at the Madison VA through the Precision Oncology Program has increased uptake and awareness of CGP results and potential treatment options, improving the access of targeted treatments and clinical trial opportunities for Veterans with cancer.
Background
The William S. Middleton Memorial Veterans Hospital (Madison VA) prioritized the goal of ensuring patients with cancer are receiving guideline-based precision oncology care, including comprehensive genomic profiling (CGP) and germline genomics consultation based on evidence-based medicine and the VA Clinical Pathways. A local Precision Oncology Program was created to assist in review of CGP results including documentation in the electronic medical record (EMR) and recommendations for treatment or additional testing as appropriate. The program, which began in February 2024, focused on patients with prostate cancer initially. This was expanded to all genitourinary cancers in April 2024, non-small cell lung cancers (NSCLC) in August 2024, and all cancers in Dec 2024.
Results
Since the implementation of the Madison VA Precision Oncology Program, CGP was reviewed for 73 unique Veterans leading to 281 recommendations including: 25 FDA approved therapies, 2 off-label standard of care treatment options, 11 patients with potential clinical trial eligibility at the Madison VA. Forty-eight patients had no actionable mutations and 44 were recommended for additional germline genetics counseling. For patients with metastatic prostate cancer, after 1 year of program implementation, an increase was seen in the percentage of patients receiving guideline-based CGP, the percentage of actionable alterations identified, and the percentage of patients identified as potentially eligible for a clinical trial open at the Madison VA based on CGP. The percentage of patients with an interfacility consult to the Clinical Cancer Genetics Service was also increased. For patients with metastatic NSCLC, after 6 months of program implementation, an increase was seen in the percentage of patients appropriately receiving CGP, the percentage of actionable alterations identified, and the percentage of patients on targeted therapy. In all cases where an actionable alteration was not being targeted, the treatment option was not yet appropriate for the stage of disease.
Conclusions
The implementation of preemptive review of all CGP results at the Madison VA through the Precision Oncology Program has increased uptake and awareness of CGP results and potential treatment options, improving the access of targeted treatments and clinical trial opportunities for Veterans with cancer.
Background
The William S. Middleton Memorial Veterans Hospital (Madison VA) prioritized the goal of ensuring patients with cancer are receiving guideline-based precision oncology care, including comprehensive genomic profiling (CGP) and germline genomics consultation based on evidence-based medicine and the VA Clinical Pathways. A local Precision Oncology Program was created to assist in review of CGP results including documentation in the electronic medical record (EMR) and recommendations for treatment or additional testing as appropriate. The program, which began in February 2024, focused on patients with prostate cancer initially. This was expanded to all genitourinary cancers in April 2024, non-small cell lung cancers (NSCLC) in August 2024, and all cancers in Dec 2024.
Results
Since the implementation of the Madison VA Precision Oncology Program, CGP was reviewed for 73 unique Veterans leading to 281 recommendations including: 25 FDA approved therapies, 2 off-label standard of care treatment options, 11 patients with potential clinical trial eligibility at the Madison VA. Forty-eight patients had no actionable mutations and 44 were recommended for additional germline genetics counseling. For patients with metastatic prostate cancer, after 1 year of program implementation, an increase was seen in the percentage of patients receiving guideline-based CGP, the percentage of actionable alterations identified, and the percentage of patients identified as potentially eligible for a clinical trial open at the Madison VA based on CGP. The percentage of patients with an interfacility consult to the Clinical Cancer Genetics Service was also increased. For patients with metastatic NSCLC, after 6 months of program implementation, an increase was seen in the percentage of patients appropriately receiving CGP, the percentage of actionable alterations identified, and the percentage of patients on targeted therapy. In all cases where an actionable alteration was not being targeted, the treatment option was not yet appropriate for the stage of disease.
Conclusions
The implementation of preemptive review of all CGP results at the Madison VA through the Precision Oncology Program has increased uptake and awareness of CGP results and potential treatment options, improving the access of targeted treatments and clinical trial opportunities for Veterans with cancer.
CDK7 Inhibition in Patient-Derived Organoid Modeling of Biliary Tract Cancers
Background
Biliary tract cancers (BTC) represent an important rare cancer type in Veterans. The heterogeneity of BTC has revealed distinct molecular subtypes, however a majority of patients remain without precision-based targeted therapeutics. Epigenomic remodeling has been considered as a shared mechanism of therapeutic resistance. Cyclin dependant kinase 7 (CDK7) is an emerging therapeutic target that functions by phosphorylation of RNA polymerase II and cell cycle progression. Here, we investigate CDK7 inhibition using small molecule inhibition (SY-5609) across a panel of BTC organoid models.
Methods
PCOs were expanded from patient-derived tissues and shared models provided from the NCI. Organoid response was tracked from growth using Z-stacked high content imaging (Cytation5) to track individual organoid growth and established viability markers of Caspase-3/7 (C3/7) and ToPro3, for induced apoptosis and necrosis for phenotypic screening. Treatment groups included media control, positive control (cycloheximide) 200uM continuous, gemcitabine (gem) 10uM 24h, cisplatin (cis) 5uM 48h, combination gem+cis, and SY-5609 10nM 144h. Glass’s delta was used to standardize effect size relative to media control.
Results
Patient-derived cancer organoids were generated across four unique models including pathogenic (A-B) IDH1 p.R132G, (C) FGFR2-HPGDS fusion and (D) non-targetable molecular profile (CCNE1 amplified, BRCA1 splice variant). In the non-targeted model, CDK7 inhibition achieved growth arrest +2.0% (SY-5607) v. +43.0% (media control) with effect size >1.1. This response was similar to standard of care gem+cis with growth of +1.5% and augmented using the combination of gem+SY-5609 -3.1% with effect size of >1.3. When treated with CDK7 inhibition, persistent growth was seen across models of IDH1 mutant and FGFR2-HPGDS2 fusion cancers. High content imaging revealed subclonal populations with failed induction of apoptosis and necrosis at 144h, suggestive of the critical need to address intrinsic resistant populations to both SOC chemotherapy and novel targeted strategies.
Conclusions
Across a diversity of BTC cancer models, CDK7 inhibition was found to achieve growth arrest in a CCNE1 amplified cancer model. High content imaging of organoids can identify subclonal resistant populations as a critical unmet need in future therapeutic development. Ongoing work is adapting these techniques to multiple small molecule inhibitors that target transcription including EZH1/2 and CDK9.
Background
Biliary tract cancers (BTC) represent an important rare cancer type in Veterans. The heterogeneity of BTC has revealed distinct molecular subtypes, however a majority of patients remain without precision-based targeted therapeutics. Epigenomic remodeling has been considered as a shared mechanism of therapeutic resistance. Cyclin dependant kinase 7 (CDK7) is an emerging therapeutic target that functions by phosphorylation of RNA polymerase II and cell cycle progression. Here, we investigate CDK7 inhibition using small molecule inhibition (SY-5609) across a panel of BTC organoid models.
Methods
PCOs were expanded from patient-derived tissues and shared models provided from the NCI. Organoid response was tracked from growth using Z-stacked high content imaging (Cytation5) to track individual organoid growth and established viability markers of Caspase-3/7 (C3/7) and ToPro3, for induced apoptosis and necrosis for phenotypic screening. Treatment groups included media control, positive control (cycloheximide) 200uM continuous, gemcitabine (gem) 10uM 24h, cisplatin (cis) 5uM 48h, combination gem+cis, and SY-5609 10nM 144h. Glass’s delta was used to standardize effect size relative to media control.
Results
Patient-derived cancer organoids were generated across four unique models including pathogenic (A-B) IDH1 p.R132G, (C) FGFR2-HPGDS fusion and (D) non-targetable molecular profile (CCNE1 amplified, BRCA1 splice variant). In the non-targeted model, CDK7 inhibition achieved growth arrest +2.0% (SY-5607) v. +43.0% (media control) with effect size >1.1. This response was similar to standard of care gem+cis with growth of +1.5% and augmented using the combination of gem+SY-5609 -3.1% with effect size of >1.3. When treated with CDK7 inhibition, persistent growth was seen across models of IDH1 mutant and FGFR2-HPGDS2 fusion cancers. High content imaging revealed subclonal populations with failed induction of apoptosis and necrosis at 144h, suggestive of the critical need to address intrinsic resistant populations to both SOC chemotherapy and novel targeted strategies.
Conclusions
Across a diversity of BTC cancer models, CDK7 inhibition was found to achieve growth arrest in a CCNE1 amplified cancer model. High content imaging of organoids can identify subclonal resistant populations as a critical unmet need in future therapeutic development. Ongoing work is adapting these techniques to multiple small molecule inhibitors that target transcription including EZH1/2 and CDK9.
Background
Biliary tract cancers (BTC) represent an important rare cancer type in Veterans. The heterogeneity of BTC has revealed distinct molecular subtypes, however a majority of patients remain without precision-based targeted therapeutics. Epigenomic remodeling has been considered as a shared mechanism of therapeutic resistance. Cyclin dependant kinase 7 (CDK7) is an emerging therapeutic target that functions by phosphorylation of RNA polymerase II and cell cycle progression. Here, we investigate CDK7 inhibition using small molecule inhibition (SY-5609) across a panel of BTC organoid models.
Methods
PCOs were expanded from patient-derived tissues and shared models provided from the NCI. Organoid response was tracked from growth using Z-stacked high content imaging (Cytation5) to track individual organoid growth and established viability markers of Caspase-3/7 (C3/7) and ToPro3, for induced apoptosis and necrosis for phenotypic screening. Treatment groups included media control, positive control (cycloheximide) 200uM continuous, gemcitabine (gem) 10uM 24h, cisplatin (cis) 5uM 48h, combination gem+cis, and SY-5609 10nM 144h. Glass’s delta was used to standardize effect size relative to media control.
Results
Patient-derived cancer organoids were generated across four unique models including pathogenic (A-B) IDH1 p.R132G, (C) FGFR2-HPGDS fusion and (D) non-targetable molecular profile (CCNE1 amplified, BRCA1 splice variant). In the non-targeted model, CDK7 inhibition achieved growth arrest +2.0% (SY-5607) v. +43.0% (media control) with effect size >1.1. This response was similar to standard of care gem+cis with growth of +1.5% and augmented using the combination of gem+SY-5609 -3.1% with effect size of >1.3. When treated with CDK7 inhibition, persistent growth was seen across models of IDH1 mutant and FGFR2-HPGDS2 fusion cancers. High content imaging revealed subclonal populations with failed induction of apoptosis and necrosis at 144h, suggestive of the critical need to address intrinsic resistant populations to both SOC chemotherapy and novel targeted strategies.
Conclusions
Across a diversity of BTC cancer models, CDK7 inhibition was found to achieve growth arrest in a CCNE1 amplified cancer model. High content imaging of organoids can identify subclonal resistant populations as a critical unmet need in future therapeutic development. Ongoing work is adapting these techniques to multiple small molecule inhibitors that target transcription including EZH1/2 and CDK9.