The overarching goal of my research is to understand the mechanisms underlying the maintenance of genome stability in mammalian cells, and how impairments of these mechanisms cause diseases such as cancer and neurological disorders. Based on this foundational understanding, we aim to find new targets mainly for cancer therapy as well as improve current therapies. Slightly more specifically, the main projects of the lab deal with A) What causes familial breast and ovarian cancer development? B) New mechanisms underlying genome maintenance.
Merits of the lab:
Cellular feedback systems ensure genome maintenance to suppress diseases such as familial breast and ovarian cancers. We are actively uncovering the key players, among our key findings are:
a) CtIP (RBBP8) genetic variants may predispose to early-onset breast cancer by compromising genome integrity
b) New CRISPR-method to uncover the function of genetic variants, especially with focus on early-onset breast cancer. This is in part focused on the challenging hypomorphic missense variants.
c) The emerging cancer target WEE1 kinase limits CDK activity, accordingly, the WEE1-CDK axis controls multiple key pathways including several DNA repair pathways.
d) Further, WEE1 kinase guards genome stability by suppressing a cellular nuclease that promotes DNA degradation when replication is challenged
e) New concepts in genome maintenance control with focus on the G2 cell cycle checkpoint, which is pivotal for cancer cell responses to most therapies.
Why do we want medical doctors?
We have very close connections with the clinic having several joint projects with the Center for Genome Medicine (Copenhagen General Hospital). Thus, our two M.D. and M.Sc. environments form a coherent and structured platform with exchanges and interactions at all levels. Personnel frequently exchange between the two places, we jointly craft projects/grants, we publish together and we have monthly meetings to discuss progress and challenges in an open form. A recruited EMERALD fellow would of course be deeply integrated into this environment.
For most mutations identified in cancers, we have no idea of their disease relevance. This is a major health issue, in particular for breast and ovarian cancer, where hereditary predispositions contribute substantially. With the current proposal, we suggest developing a transforming solution to this issue focusing on emerging putative driver genes and variants in early-onset breast and ovarian cancer. These research questions are at the very heart of the established close collaboration between my team and the clinical Centre for Genomic Medicine at the Copenhagen General Hospital. We have already set this up for the important BRCA1 and BRCA2 genes. Thus, the focus of the EMERALD project fellow will be to uncover key pathogenic factors in non-BRCA1/2 familial cancers.
How we will do it?
Our approaches are based on our newly invented quantitative CRISPR-Cas9 technology, CRISPR-Select, which enables functional-mechanistic clarification of cancer-derived genetic variants. The new putative genetic underpinnings are discovered at the Centre for Genomic Medicine at the Copenhagen General Hospital (which includes genetic variant data from numerous international network collaborators). Thus, the PhD student will dissect; 1) the pathogenic potential of cancer-associated variants in newly identified genes (i.e. non-BRCA1/2). 2) Therapy response impact of the newly identified variants with a focus on PARP inhibition and platinum compound chemotherapy. 3) Mechanistic role for one of the identified new genes.
Why is this important?
Transforming the approaches to VUS will have huge benefits, in particular, with expected expansion into the clinical entities that find the methodology relevant. CRISPR-SurF is at the heart of precision medicine, and it can assist doctors in decision-making and counselling options on 1) whether or not to remove the breast and ovaries from the patient and female relatives with the variant, 2) whether the patient should be treated with PARP (Poly ADP-ribose polymerase) inhibitor that is highly effective in patients with BRCA-loss or 3) whether life-long surveillance of patient should be implemented. As the methodology will develop further, we expect to precisely determine genetic variant roles for all patients where relevant, thereby expanding well beyond the familial breast and ovarian cancers.
Who is a good fit for the project?
The person should have an interest in cancer and genotype-phenotype interactions. Prior experience with CRISPR approaches would be preferred.
Interest in molecular genetics and basic cancer research would be relevant.
IDIBAPS#1 – Developing and investigating computing, machine learning and physiological modelling for understanding each individual heart towards personalised medicineDavid Brena2022-05-17T10:37:53+00:00