Flash Talk & Poster Presentation 32nd Lorne Cancer 2020

Using genomics and pre-clinical models to improve treatment options for patients with rare cancers (#106)

Holly E Barker 1 2 , Cassandra Vandenberg 1 2 , Amandine Carmagnac 1 , Damien Kee 1 3 , Emily O'Grady 4 , Gayanie Ratnayake 5 , Kym Pham 2 , Joseph Vissers 2 , Oliver Hofmann 2 , Sean Grimmond 2 , Matthew Wakefield 1 2 , Tony Papenfuss 2 3 4 , Clare Scott 1 2 3 5
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. The University of Melbourne, Melbourne, VIC, Australia
  3. The Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  4. The Walter and Eliza Hall Institute of Medical Research, MelbourneParkville, VIC, Australia
  5. Royal Women's Hospital, Parkville, VIC, Australia

New therapies for rare cancers are lacking, due to insufficient pre-clinical data and accrual difficulties for traditional clinical trials1. We hypothesise that rare cancers have a relatively clean genetic background compared to more common cancers, making them more amenable to targeted therapies2.

The WEHI Stafford Fox Rare Cancer Program (WEHI-SFRCP) provides streamlined national access, including remote consent capability, inclusive eligibility criteria, a REDCap database and a global materials transfer agreement. Since the Program was initiated at the end of 2016, we have consented 210 patients with 64 different types of rare cancer. We perform whole genome sequencing (WGS) on the most aggressive subset, with putative targetable aberrations based on pre-clinical data identified in almost all cases, and matched drugs available in 46% of gynaecological cases. Simultaneously, pre-clinical models of these rare cancers, such as organoids, patient-derived xenografts (PDX) and genetically-engineered mouse models (GEMM), are being derived, enabling us to determine whether targeting these actionable aberrations is indeed effective.

Examples of rare gynaecological cancers where we have developed pre-clinical models to test specific targeted therapies are ovarian carcinosarcoma (OCS), uterine leiomyosarcoma (uLMS), and high-grade serous endometrial cancer (HGSEC). We have recruited 9, 28 and 24 patients with these rare tumours, respectively, and developed pre-clinical models to test specific drugs based on molecular data. Analysis of WGS enabled highly efficacious PARP inhibitor treatment for a woman with uLMS, who had exhausted all other options. Two cases of rare gynaecological neuroendocrine tumours for which we have WGS and for one, a corresponding PDX, have resulted in never-responder and cell of origin studies respectively.

The WEHI-SFRCP provides clinically relevant research options for those with rare cancers nation-wide, enabling matched therapies to be identified for individual patients as well as developing pre-clinical research projects to further understand specific rare cancers, underpinning new treatment options for future patients.

  1. 1 Barker, H. E. & Scott, C. L. Genomics of gynaecological carcinosarcomas and future treatment options. Semin Cancer Biol, doi:10.1016/j.semcancer.2019.10.006 (2019).
  2. 2 Barker, H. E. & Scott, C. L. Preclinical rare cancer research to inform clinical trial design. Nat Rev Cancer 19, 481-482, doi:10.1038/s41568-019-0172-2 (2019).