Apr 11, 2023
By Jasenka Piljac Zegarac, PhD
Alan Ashworth, PhD, FRS, president of the UCSF Helen Diller Family Comprehensive Cancer Center and senior vice president for cancer services at UCSF Health, has been honored with the Science of Oncology Award for his innovative and translational research accomplishments and his role in the development of PARP inhibitors for cancer.
“This is a lovely recognition of the work that has been going on for decades, not just for me, but the entire team,” he said. “I’ve been privileged to work with many great people over the years, and [this award] is a recognition for all the hard work that’s been put in to get us to this stage and, of course, all the patients who have been involved in the clinical trials that have led to drug approvals.”
A Pioneer of Targeted Therapy for Cancer
Dr. Ashworth received his PhD in biochemistry from the University of London, in the United Kingdom. After spending 28 years as a researcher at the Institute of Cancer Research (ICR) in London, in 2015 he transferred to UCSF where he is currently professor of medicine and the E. Dixon Heise Distinguished Professor in Oncology.
A pioneer of targeted therapy, Dr. Ashworth was instrumental in the discovery of the BRCA2 gene, which is today widely used in risk stratification of individuals at risk of developing breast and ovarian cancers.1 His team is also credited for identifying ways to exploit genetic weaknesses of cancer cells with mutated BRCA1 or BRCA2 genes using synthetic lethality, which led to PARP inhibition as a novel therapeutic modality in cancer.2 Today, PARP inhibitors such as olaparib, rucaparib, talazoparib and niraparib are used to treat patients with breast, ovarian, prostate, and pancreatic cancers with BRCA mutations.
In recognition of his breakthrough research accomplishments, he has received numerous prizes including the ESMO Lifetime Achievement Award, the Meyenburg Prize, the Genetics Society of America Medal, a Brinker Award for Scientific Distinction from Susan G. Komen, and the inaugural Basser Global Prize.
Starting Out at the Institute of Cancer Research
Dr. Ashworth credits his friend and colleague Professor Chris Marshall from the ICR for guiding him on his path of cancer discovery. “He was one of the pioneers in the RAS field,” he said. “We did not directly work together much, but we were good friends. He influenced my scientific thinking very strongly. He also encouraged me to be bold and to take risks.”
His work on BRCA2 came about through being drawn into a collaboration led by Michael Stratton, FMedSci, FRS, of the Wellcome Sanger Institute in the United Kingdom. “My lab became involved because we were good at identifying genes,” he said. “Why this project was different was that we identified a gene that turned out to be very important clinically and, almost immediately, changed the way that people were treated.”
In some people, he added, the discovery of BRCA1 or BRCA2 mutations led to preventative surgery; in others, eliminating the possibility of a mutation meant that these individuals were not at additional significant risk of developing cancers.
A Shift Toward Translational Research
The clinical impact of these early discoveries sparked his continued interest in translational cancer research.
“I started off as a very basic biologist, but this was the moment where I decided to kind of redirect my efforts to both basic biology but also basic biology with a translational aspect,” he said. “That led me to then work closely with clinicians to understand the clinical perspective, pathologists, radiation oncologists, and others… to build that team that could think in a very translational way.”
His current research is focused on understanding the genetic interactions in cancer and how they can be leveraged for cancer therapy.
“Obviously, PARP-BRCA was a synthetic lethal interaction that became important in the development of PARP inhibitors and their eventual U.S. Food and Drug Administration approval,” he said. “So, we continue to study those, but we also look for other types of synthetic lethal interactions both in cancer cells but also increasingly in immune cells.
“We’ve become interested in how one knocks out genes in primary T cells and using that information to develop better immunotherapies,” he added.
As a senior vice president for cancer services at UCSF, he said that one of his goals is to “link the [basic] research to the clinical service and rapidly move things from the lab to the clinic.”
Facing Remaining Challenges
Despite the profound effects that targeted therapies have had on the treatment of cancer, multiple challenges remain in harnessing the true power of these therapies. One is expanding the utility of already available PARP inhibitors to other cancers.
“The principle of using mutations to define treatment in hereditary cancers is well established, but we could apply the agents more broadly,” he said. “So, the utility of PARP inhibitors can continue to be expanded.”
BRCA2 was originally discovered in 1995,1 PARP inhibitors with lethal interaction were first reported in 2005,3 and the clinical trial publication confirming the efficacy of a PARP inhibitor in adjuvant breast cancer was published in 2021.4 “It’s taken more than 25 years to get to our original aim of identifying genes so that we could develop new treatments that are hopefully effective at saving lives,” he said.
One of the focus areas of his current research is developing cellular therapies capable of effectively eliminating solid tumor cells.5,6
“There’s multiple challenges there,” he said, such as, “can you get T cells into the tumor, and can you make sure that they’re actually effective and don’t become exhausted? But I think that these are challenges that must be overcome, and [when they are overcome] it’s quite likely then that cellular therapies will make a big impact in solid tumors.”
Other challenges include optimizing the CAR T-cell engineering process to include combinatorial antigens, scaling the manufacturing process, and reducing the cost associated with CAR T-cell production. He is hopeful that off-the-shelf allogeneic therapies currently being developed for hematological malignancies will help overcome at least some of these issues, including those associated with the speed and cost of production.
During his Science of Oncology Award address at the ASCO Annual Meeting on June 5, Dr. Ashworth will discuss lessons learned from applying genetics in the development of cancer therapeutics.
“Given that it’s been a long journey, we’re trying to think of what we did right (and wrong) and how it can be applied to other situations, what are the lessons learned?” he asked.
- Wooster R, Bignell G, Lancaster J, et al. Identification of the breast cancer susceptibility gene BRCA2 [published correction appears in Nature 1996 Feb 22;379(6567):749]. Nature. 1995;378(6559):789-792. https://doi.org/10.1038/378789a0.PubMed
- Lord CJ, Ashworth A. PARP inhibitors: Synthetic lethality in the clinic. Science. 2017;355(6330):1152-1158. https://doi.org/10.1126/science.aam7344.PubMed
- Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917-921. https://doi.org/10.1038/nature03445.PubMed
- Tutt ANJ, Garber JE, Kaufman B, et al. Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer. N Engl J Med. 2021;384(25):2394-2405. https://doi.org/10.1056/NEJMoa2105215.PubMed
- Carnevale J, Shifrut E, Kale N, et al. RASA2 ablation in T cells boosts antigen sensitivity and long-term function. Nature. 2022;609(7925):174-182. https://doi.org/10.1038/s41586-022-05126-w.PubMed
- Shifrut E, Carnevale J, Tobin V, et al. Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function. Cell. 2018;175(7):1958-1971.e15. https://doi.org/10.1016/j.cell.2018.10.024.PubMed