CCBIO Seminar - Mari Kyllesø Halle

Foreleser: Mari Kyllesø Halle
Tittel: Decoding the Landscape of Cancer Vulnerabilities in high-risk Cervical Cancer
Vert: Stein-Erik Gullaksen
Sted: Auditorium 4, BB-bygget, Bergen
Når: 29. august 2024 kl. 14.30-15.30

Påmelding er ikke nødvendig. 

Short bio: Mari Kyllesø Halle is a molecular biologist with the Bergen Gynecological Cancer Research Group (CCBIO). She has recently initiated a four-year project funded by the Norwegian Cancer Society aiming to decode the landscape of vulnerabilities in high-risk cervical cancer. By utilizing CRISPR-Cas12 dependency and drug sensitivity screens, followed by in vitro and in vivo drug testing, she seeks to identify new treatments for high-risk cervical cancer patients. Mari has extensive experience in biomarker detection and multi-omics analysis within uterine cancers.

Abstract: Following funding of a four-year research project (Norwegian Cancer Society) focusing on rare histologies we are fine-mapping rare cervical cancer (CC) tumors alongside corresponding relapse biopsies by assembling all genomic, transcriptomic, radiomic, molecular, and clinicopathological patient data collected since 2001. To increase power of detecting targetable alterations in rare subgroups, we teamed up with Prof. Santin from Yale University (Connecticut, US) who collected and sequenced 65 NETs, including 10 NETs from our cohort, identifying 100 common oncogenic drivers recently published in PNAS. We will perform preclinical targeted drug testing towards these drivers at Yale. In parallel, we will establish our own organoid library from all consenting CC patients admitted to Haukeland University Hospital (HUH) during the project period, perform CRISPR-Cas12 dependency screens and design drug sensitivity panels based on identified drivers. Subsequently, we are utilizing the extensively characterised local (UiB) CC patient cohort (approaching 650 patients) to identify subtype-specific clinically relevant response markers. 

Firstly, we have started investigating targets for antibody drug conjugates (ADCs), which represent a new group of cancer drugs providing promising response rates across multiple cancer types. 525 primary and 194 metastatic cervical cancer lesions were investigated for membrane expression of the ADC targets TF, TROP2 and NECTIN4 in relation to clinicopathological data and patient outcome. 
TF, TROP2, and NECTIN4 showed tumor specific expression and were overexpressed (3+) in 29%, 37% and 4% and highly expressed (≥2+) in 48%, 68% and 12% of the tumors, respectively. TROP2 negative expression associated with poor outcome (p=0.02). High TF and NECTIN4 was predominantly observed in squamous tumors (p<0.001) of low-grade histology (p<0.042) and squamous- or adenosquamous- histology (p<0.001). High TROP2 expression predominated within tumors with vascular space invasion (p=0.009) and squamous-, adenosquamous- or undifferentiated- histology (p<0.001). High TF and TROP2 expression were maintained also within the metastatic lesions. 

Conclusions so far: TF, TROP2 and NECTIN4 are highly expressed in cervical cancer. High expression levels are maintained within metastatic and recurrent lesions. Clinical trials evaluating the safety and efficacy of ADCs are highly relevant in cervical cancer.