Nancy McKinstry, former Vancouver investment advisor and vice president at Odlum Brown, embarks on what she calls a “second life” after a diagnosis of clear cell ovarian cancer in 2005. Nancy reflects on the past 18 years with gratitude, and now facing a recent recurrence of the same cancer, she is more committed than ever to giving back.
Alongside her husband, Greg, she established the Nancy McKinstry Endowment Fund for Ovarian Cancer Research, held at the BC Cancer Foundation. This endowment fund is dedicatedto advancing research in ovarian cancer and aims to attract and retain the brightest minds in ovarian cancer research, driving forward impactful advancements.
This year, we are proud to congratulate Vanessa Chan and Forouh Kalantari, recipients of the 2024 Nancy McKinstry Trainee Excellence Award, for demonstrating a high degree of research
excellence and potential in ovarian cancer research.
Vanessa Chan
Vanessa is a PhD Student at UBC Pharmaceutical Sciences. Her passion for cancer research was sparked by personal and educational experiences, including early mentorship at BC Cancer and her research experiences during her undergraduate studies. Motivated by the challenges of poor survival rates and treatment toxicity in ovarian cancer, she has focused her current work on advancing innovative immunotherapies to address these critical gaps.
Project Summary:
According to the Canadian Cancer Society, 3100 women in Canada will be diagnosed with ovarian cancer and 1950 women will die from it in 2023. Unfortunately, about 58% of ovarian cancers are diagnosed at the metastasized stage and the 5- year survival rate is only 30.2%.
Conventionally, the treatment for peritoneal spread of ovarian cancer includes cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). However, disease recurrence was observed in 21.6% of patients,and 60% of those were seen in the peritoneal cavity. Immune checkpoint inhibitor (ICI)-based immunotherapy has been implicated to be beneficial in ovarian cancer, but its efficacy in phase III trials has yet to be demonstrated.
Additionally, ICIs cause paraneoplastic neurological syndromes in ovarian cancer patients, limiting their clinical benefit. The information suggests a targeted approach to deliver immunotherapy will improve the efficacy and safety for patients with ovarian cancer.
L1 is a cationic liposome that has been previously demonstrated by us to successfully localize an immune-stimulating drug, Resiquimod (R848), in the peritoneal cavity compared to other formulations. Intraperitoneal (IP) injection of L1-R848 locally increased levels of interferon (IFN) alpha in the peritoneal fluid in a mouse model of peritoneal metastasis of colorectal cancer. Through dosing regimen optimization, we observed an 80% cure rate by the L1-R848 therapy, and these cured animals developed specific T cell immunity against the same tumor.
We propose to examine efficacy of L1-R848 as a single therapy and in combination with anti-PD-1 in a syngeneic ovarian cancer model in mice. By direct delivery and retention in the peritoneal cavity, the localized action of L1-R848 holds the promise of reducing systemic side effects commonly associated with current immunotherapy. Therefore, this targeted approach may not only enhance the therapeutic efficacy but also improve the overall quality of life for patients undergoing treatment. Furthermore, the prospect of increased long-term survival rates and the potential development of immune memory, as suggested by the subcutaneous rechallenge experiment, brings hope for sustained protection against cancer recurrence.
Forouh Kalantari
Forouh Kalantari’s dedication to cancer research began during her clinical laboratory internship in Iran, where her interactions with cancer patients inspired her to pursue advanced training. After completing a master’s degree in cancer biology at the University of Manitoba, she is now a PhD candidate at the University of British Columbia, working under the mentorship of Dr. David Huntsman. Her long-term aim is to advance ovarian cancer treatment and reduce its global burden.
Project Title: G6PD-dependant metabolism: A potential targetable pathway in ARID1A mutant clear cell ovarian cancer
Project Summary:
Clear Cell Ovarian Carcinoma (CCOC) is an uncommon ovarian carcinoma which accounts for about 12% of all ovarian cancers in North America1. CCOC is inherently resistant to platinum/taxane chemotherapy, and late stage CCOCs have worse prognosis than other ovarian cancer histotypes. Our lab discovered inactivating mutations of ARID1A in about 50% of CCOC, often co-occurring with a PIK3CA activating mutations.
ARID1A mutations occur with high prevalence in precursor lesions adjacent to cancer sites, suggesting this mutation is an early event in tumor development. Our results from single cell RNA sequencing demonstrated that S100A4 is upregulated in our ARID1A mutant organoid models, these data correlated with the increased accessibility of the chromatin of the S100A4 gene of the mutant organoids observed in scATAC-seq. We further validated these data in wildtype and ARID1A mutant CCOC cell lines.
Additionally, S100A4 immunohistochemistry on CCOC tissue microarrays showed significant association between S100A4 expression and ARID1A loss. S100A4 is a calcium binding protein which interacts with structural proteins to promote metastasis of cancer cells, however, the exact mechanism is still unknown. In order to understand the mechanism of S100A4 in our model, we performed immunoprecipitation of S100A4 followed by mass spectrometry analysis (IPMS) in 4 different ARID1A mutant cancer cell lines to analyse the interactome partners of S100A4. The results demonstrated Glucose -6-phosphate dehydrogenase (G6PD) to interact with S100A4 in all 4 cell lines. G6PD is a rate limiting enzyme in pentose phosphate pathway (PPP) that supplies the energy to the cells in oxidative damage response by maintaining the level of NADPH. The preliminary experimental analysis conducted on S100A4 WT and CRISPR knockout cells, following treatment with a G6PD inhibitor, revealed notable reductions in specific glycolytic metabolites known to play roles in promoting cancer cell proliferation. The observed decreases in glycolysis intermediates highlights the significance of G6PD activity in regulating metabolic flux and targeting this pathway to inhibit cancer cell metabolism and proliferation.
AIM 1: To investigate the impact of G6PD inhibition on cancer cell survival, proliferation, migration and colony formation potential. We have generated various S100A4 Crispr KO cell lines alongside non-targeting controls and have validated successful depletion of S100A4 protein. We will assess cell survival post-G6PD inhibitor treatment using crystal violet and MTT assays. Additionally, we will to monitor cell proliferation using the Incucyte at different time points. To evaluate migratory potential, we will perform wound healing assays. For colony formation assays, cells will be seeded at low densities, subjected to G6PD inhibitor treatment for one week, followed by crystal violet staining to quantify the number and size of colonies formed.
AIM 2: To investigate novel metabolomic pathways under G6PD inhibition. The preliminary experimental analysis conducted on S100A4 WT and CRISPR knockout cells, following treatment with a G6PD inhibitor, revealed notable reductions in specific glycolytic metabolites. In collaboration with Dr. Ramon Klein Geltink, we will use mass spectrometry techniques in S100A4 WT and KO cells treated with G6PD inhibitor and compare it to metabolomic profile from ARID1A WT cells. This will provide insights
into metabolic regulation associated with ARID1A and S100A4 mutation and may uncover potential therapeutics targets.
Significance: Previous reports have also shown an interplay between G6PD and SWI/SNF complex mutation
in non small cell lung carcinoma and G6PD inhibitors have increased sensitivity to oxidative stress. Understanding the biological function of S100A4 and G6PD interaction may lay the groundwork for the development of new therapeutics for ARID1A mutant gynecological cancer patients.
Upcoming Events…
The Nancy McKinstry Endowment Fund for Ovarian Cancer Research has now surpassed $400,000. We are thrilled to announce an upcoming reception to celebrate Nancy and her incredible contributions.
Nancy will also be featured in an upcoming interview on the GOSH Podcast, where she will share her personal journey with ovarian cancer– from her initial diagnosis to her recent recurrence, everything in between. The episode is set to be released in January, so stay tuned!