Synopsis

An underlying hallmark of cancers is genomic instability and a greater propensity to accumulate DNA damage. Historical cancer therapy by radiotherapy and DNA-damaging chemotherapy is based on this principle but is accompanied by significant collateral damage to normal tissue and unwanted side effects. Targeted therapy based on inhibiting the DNA damage response (DDR) in cancers offers the potential for a greater therapeutic window by tailoring treatment to patients with tumors lacking specific DDR functions.

The DNA damage response (DDR) in cancer cells differs in at least four aspects compared to those of normal cells, namely the loss of one or more DDR pathway or capability leading to greater sensitivity to DNA damaging agents, increased levels of replication stress, increased potential for immune priming and the potential for a DDR dependency that could lead to sensitivity to a single DDR agent. An example of the latter is the synthetic lethality and clinical activity of PARP inhibitors in tumours with homologous recombination repair deficiencies such as BRCA mutant cancers.

This meeting will focus on the current approaches of targeting DDR to generate new cancer therapies from building on the clinical success of PARP inhibitors, identifying ways to exploit replication stress in cancers, enhance the potential for immunotherapy combinations as well as enhance the activity of targeted DNA damaging agents such as antibody drug conjugates (ADCs) and radioconjugates.

The meeting aims to bring together academics, translational biologists and clinicians who are working towards developing therapies based on targeting DDR in cancer and represents an excellent opportunity for networking and gaining broader insights into this exciting area of cancer biology and therapeutics through a number of panel discussions as well as presentations.

Key Sessions

• Current status of DDR therapeutics
• Building on the success of PARP inhibitors
• DDR therapeutic approaches based on DDR synthetic lethality
• Targeting replication stress in cancers
• Combining DDR inhibition with DNA damaging agents (chemotherapy/ADCs and potentiation of radiation/radio-conjugates)
• Combining DDR inhibitors with immunotherapy
• Enabling capabilities for DDR therapeutics
• The next generation of DDR new targets

Panel Discussions

• Challenges of therapeutic preclinical and clinical development
• Patient stratification and optimisation of drug safety /therapeutic index
• Career options in DDR drug discovery and development

Confirmed Speakers

Thanos Halazonetis (University of Geneva)
LANDSCAPE OF THERAPEUTIC APPROACHES TO TARGET DNA REPLICATION STRESS IN CANCER
Tim Yap (MD Anderson Cancer Center)
TARGETING THE DDR IN THE CLINIC: STATE OF THE ART
Steve Jackson (Cancer Research UK Cambridge Institute)
CELLULAR RESPONSES TO DNA DAMAGE: MECHANISTIC INSIGHTS AND MEDICAL IMPLICATIONS
Katie Chapman (Tessellate BIO)
SYNTHETIC LETHALITY OF FANCM INHIBITION IN ALT CANCERS
George Au-Yeung (Peter MacCallum Cancer Centre)
TARGETING DNA DAMAGE RESPONSE IN CYCLIN E1 OVER-EXPRESSED HIGH GRADE SEROUS OVARIAN CANCER
Eric Brown (University of Pennsylvania)
IMPACT OF DNA REPEAT SILENCING ON ATR INHIBITOR-DRIVEN GENOMIC BREAKS AND DRUG RESPONSES
Josep Forment (AstraZeneca)
TARGETING THE DNA DAMAGE RESPONSE IN CANCER TREATMENT
Helen Robinson (Artios Pharma)
Triparna Sen (Icahn School of Medicine at Mount Sinai)
INTRATUMORAL STING PATHWAY ACTIVATION ENHANCES ANTI-TUMOR IMMUNE RESPONSES AND THERAPEUTIC EFFICACY OF ATR INHIBITION
Charlie Gourley (Cancer Research UK Scotland Centre)
HIGH GRADE SEROUS OVARIAN CANCER AS A REPLICATION STRESS EXEMPLAR: WHAT DOES RECENT DATA TELL US ABOUT EXTENDING POTENTIAL VULNERABILITIES?
Violeta Serra (Vall d'Hebron Institute Oncology)
HARNESSING STING SIGNALING TO OVERCOME PARP INHIBITOR RESISTANCE IN HOMOLOGOUS RECOMBINATION DEFICIENT BREAST CANCER
Kevin Harrington (Institute of Cancer Research)
LEVERAGING THE DNA DAMAGE RESPONSE TO OPTIMISE ANTI-TUMOUR IMMUNE RESPONSES
Alan Lau (AstraZeneca)
Magda Kordon-Kiszala (intoDNA)
Ani Michaud (Promega)
Chris Lord (Institute of Cancer Research)
UNDERSTANDING AND TARGETING PARP INHIBITOR RESISTANCE IN CANCER
Andre Nussenzweig (National Cancer Institute)
CHEMOTHERAPY TARGETS DEDUCED BY GENOMIC METHODS
Gabriele Picco (Wellcome Sanger Institute)
Luke Piggott (Debiopharm International SA)
Yves Pommier (National Cancer Institute)
RATIONALE FOR COMBINING DDR INHIBITORS WITH TUMOR-TARGETED ANTICANCER DRUGS
Simon Powell (Memorial Sloan Kettering Cancer Center)
Ian Smith (Artios Pharma)
Steve West (Francis Crick Institute)
REPLICATION FORK INSTABILITY AT CENTROMERES FOLLOWING PARP INHIBITOR TREATMENT
Michael White (IDEAYA Biosciences)
Jacob Bush (GSK)
SYSTEMS CHEMICAL BIOLOGY FOR EXPANSION OF THE DRUGGABLE PROTEOME AND VALIDATION OF THERAPEUTIC TARGETS
Kasper Fugger (UCL Cancer Institute)
MTH1 SELECTIVELY TARGETS 2-AMINO-DATP TO SAFEGUARD GENOME STABILITY
Ben Van Houten (UPMC Hillman Cancer Center)
SINGLE MOLECULE ANALYSIS OF PARP1 DNA NICK BINDING KINETICS: PROBING ALLOSTERY THROUGH INHIBITORS

Target Audience

DDR researchers/clinicians in academia, biotech, pharma and healthcare.  

Educational Need

Following the success of PARP inhibitors for the treatment of a range of Homologous Recombination Repair (HRR) deficient cancer types, considerable effort has been made to identify new chemo/radio combination opportunities and novel targetable vulnerabilities in cancers harbouring DDR deficiencies and heightened replication stress. Several of these targets and their combinations are currently in clinical trials with the promise to expand the repertoire of drugs that can be utilised for cancer therapy. This meeting will provide a unique forum for discovery scientists from academia, biotech and pharma and medical oncologists and radiologists to present and discuss their latest discoveries and clinical trial data to the community. With meet and greet sessions and panel discussions with key opinion leaders, we anticipate that this meeting will provide an ideal educational opportunity for early career scientists and clinicians who are new to or wish to enter this space. A meeting of this kind is currently lacking and would provide an ideal platform for idea exchange, networking and the establishment of new collaborations.

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