Titles and Affiliations
Nan & Lorraine Robertson Chair in Breast Cancer Research
Canada Research Chair in Molecular Oncology
Distinguished Scientist and Head, Department of Molecular Oncology,
Professor, Department of Pathology & Laboratory Medicine
Fellow, Royal Society of Canada, Life Science Division
Research area
Decoding the genomic makeup of triple-negative breast cancer to reveal actionable targets for developing new strategies to personalize therapy.
Impact
While platinum-based therapies, like cisplatin, are an effective therapy for many triple-negative breast cancers (TNBCs), new treatments are urgently needed to treat those who do not respond. One major challenge is that TNBC is a group of diseases that are not fully understood, complicating the development of targeted therapies. Dr. Aparicio’s work decoding the genome sequences of TNBC has revealed vulnerabilities that could be used to design effective targeted therapies. Specifically, his team has observed at least four distinct patterns in the DNA structure of TNBC tumors that may represent genomic instabilities and confer deficiencies in the tumors’ ability to repair DNA damage. Dr. Aparicio is using a novel approach that leverages a convergence of technologies—single cell analysis and translational medicine–bringing expertise from diverse fields to solve a difficult problem: how to recognize and defeat TNBC in the clinic.
Progress Thus Far
Dr. Aparicio and his colleagues have identified a completely new way to target TNBC using a class of drugs called G-quadruplexes (G4) that bind to folded DNA, exploiting genomic instability and repair deficiencies in these tumors. A phase I clinical trial to test one of these drug molecules, CX-5461, in patients with TNBC showed promising results which were published in the journal Nature. In addition to supporting this therapy for TNBC tumors that develop resistance to platinum therapy, they also found that DNA is vulnerable once treatment with these drugs has ended, presenting a unique window of opportunity for other DNA targeting drugs or drug combinations. Other BCRF-supported work enabled Dr. Aparicio’s team to establish a single-cell atlas of clinically normal aging breast tissue, a critical tool for investigations into how tissue risk factors may affect whether a breast cancer develops. A third area of concentration is on developing a liquid biopsy platform to sequence chemical markers on circulating tumor DNA in blood. They have already demonstrated its ability to detect cancer recurrence by up to 33.9 months before standard clinical diagnosis.
What’s next
Dr. Aparicio will continue to investigate how drug molecules like CX-5461 are retained within cells, how they alter DNA activity. They will then test combination regimens that exploit the therapeutic window opened by G4 treatment. In the next year, they will utilize the single-cell atlas they developed to gain a better understanding of the tissue risk factors that may affect whether a breast cancer develops. Building on their liquid biopsy work, Dr. Aparicio and his colleagues will assess tumor growth dynamics and recurrence monitoring and hope to give clinicians a real-time, plasma-based readout of how a tumor is behaving and responding to therapy. This work is relevant to detecting breast cancer recurrence or residual cancer burden after treatment and avoiding futile therapy. Dr. Aparicio hopes these parallel studies will converge to provide valuable information for treating and improving outcomes in patients with TNBC.
Biography
Dr. Samuel Aparicio, BM, BCh, PhD, FRCPath is the Nan & Lorraine Robertson Chair in Breast Cancer Research, holds the Canada Research Chair in Molecular Oncology, and is the recipient of the 2014 Aubrey J Tingle Prize. He is also Head of the BCCA’s Department of Breast and Molecular Oncology, and a Professor in the Department of Pathology and Laboratory Medicine at UBC.HE graduated in medicine from Cambridge undertook clinical training in Oxford, subsequently in internal medicine and pathology. After doctoral work with Sydney Brenner in Cambridge he held a Wellcome Trust Career Development Fellowship at the Wellcome/CRUK Developmental Biology Institute. From 2000-2005 he was a senior investigator in the Department of Oncology, Cambridge. He was a co-leader of the international consortium that sequenced the genome of the pufferfish Fugu rubripes in 2002 and a visiting professor at the IMCB, Singapore.
Dr. Aparicio’s research program encompasses the fields of cancer genomics, laboratory genetic models, high throughput screens, small molecule chemical probes and translational breast cancer research. His most recent work on the molecular taxonomy of breast cancer led to identification of new genes that could change the way breast cancer is diagnosed and form the basis of next-generation treatments. This discovery was preceded by another breakthrough in decoding the genetic makeup of the most-deadly form of breast cancer, known as triple negative subtype. Dr. Aparicio is also working to develop quantitative measures of clonal fitness in patients, including methods for single cell genome sequencing and PDX models of human cancer. He collaborates widely with other groups, with current projects including the genomic and biochemical analysis of lymphoma, ovarian cancer, and several rare pediatric cancers. He was a co-founder of Paradigm Therapeutics (now, Takeda Cambridge) and currently Contextual Genomics Ltd.
As a physician-scientist, the key philosophy of Dr. Aparicio’s program has been to provide a strong multidisciplinary environment for training of highly qualified personnel (HQP). His former trainees (career total 90) have gone on to success in academia: 1 institute director, 3 as PIs and others in medicine or in senior positions in industry or postgraduate education. All of his graduate students have been successful in securing national (CIHR, NSERC) or provincial (Michael Smith Foundation, CBCF BC/Yukon) competitive salary support and two of the four postdoctoral fellows are supported by independent peer reviewed salary awards from international (Australia), national (CBCF) and provincial (MSFHR) funding bodies.
Dr. Aparicio has published 172 papers in genomics and genetics of disease with >35,000 citations (H-index 77, i10 index 151). He has published in such high impact journals as: New England Journal of Medicine, Nature, Cell, Science, Nature Medicine, Nature Genetics, Nature Methods, Cell Stem Cell and Cell Metabolism.
