7:25 am Registration
8:25 am Chair’s Opening Remarks
REFLECTING ON PROGRESS: REVERSE INSIGHTS & THE NEXT STEPS FOR DDR INHIBITORS
8:30 am The Next Chapter of DDR Inhibitor Development Across Cancers
Synopsis
• Reflecting on lessons learned from updates in DDR inhibitor development in the past 12 months
• Combination therapies: overcoming toxicity challenges and PARP inhibitor resistance
• Highlighting future directions for DDR inhibitors
9:00 am Reverse Translation of First Generation Clinical PARP Inhibitors to Inform Next Generation PARPi-Based Medicines
Synopsis
• Understanding key aspects of PARPi MoA: PARP selectivity, trapping characteristics and HRD-specificity
• Exploring additional PARPi characteristics that contribute towards clinical tolerability profiles (such as secondary pharmacology and plasma vs bone marrow distribution)
9:30 am Digital: Why Aren’t Monotherapies Working? Are DDR Inhibitor Combinations the Answer? Progress, Pitfalls & Promise
Synopsis
• Challenges with DDR combinations: overlapping toxicities, contribution of components and patient selection
• Potential solutions to overcoming toxicities and maintaining efficacy with DDR combinations
• Future questions that remain in the development of rational DDR combinations
10:00 am RNA-Seq in Precision Oncology
Synopsis
RNA sequencing (RNA-Seq) is critical to developing the next generation of cancer therapies. Data from tumor gene expression is rich in biological information, including cellular composition, the tumor cell type of origin, the tumor microenvironment (TME), drug target overexpression, oncogenic pathway signaling, and prognostic/predictive cell states such as HRD. Because of this richness, it is vital to understand, leverage, and validate RNA at every stage of drug development, including target discovery and selection, molecular characterization across the patient journey, mechanistic studies, predicting and characterizing drug sensitization and resistance, clinical trial design, combined and multimodal therapeutic opportunities, trial recruitment, indication expansion, TME characterization, and CDx development
10:30 am Morning Break & Speed Networking
Synopsis
The ideal opportunity to get face-to-face with many of the brightest minds
working in the DDR field and introduce yourself to the attendees that you would
like to have more in-depth conversations with.
DISCOVERY TRACK
Novel Methods to Discover First-in-Class DDR Inhibitors for Next-Generation Targets
11:30 am Emerging Methods to Implement AI & Machine Learning in DDR Inhibitor Discovery
Synopsis
• Evaluating AI and machine learning methods implemented at multiple stages of DDR inhibitor drug discovery
• Evaluating computational methods for small molecule optimization and validating predictions
• Accounting for limited understanding of novel target function and pathway interactions
12:00 pm Novel Cell-Based Assay Development for Multi-Faceted DDR Targets
Synopsis
• Building sensitive functional and mechanistic assays for novel DDR targets
• The importance of high throughput and quantitative assays to determine compound potency, specificity and selectivity in cells
• Understanding how to develop assays for challenging DDR targets with multiple domains and functions
12:30 pm Context is key: Exploring target engagement cooperativity within the DDR pathway using live-cell NanoBRET assays
Synopsis
- Tools for exploring mode of action for DDR inhibitors in living cells
- Biomolecular interactions govern target vulnerability for PRMT5 and Pol-theta
- Quantifying uncompetitive TE at protein:DNA and protein:metabolite complexes in cells
PRECLINICAL & CLINICAL TRACK
Unravelling Combination Conundrums for DDR Inhibitors
11:30 am Pre-clinical Development PKMYT1 Inhibitor Combinations
Synopsis
• CCNE1 amplification or cyclin E overexpression renders tumor cells hypersensitive to premature CDK1 activation through inhibition of the PKMYT1 kinase with lunresertib (RP-6306): a first-in-class, potent and selective PKMYT1 inhibitor in clinical development
• Redundance in CDK1 activity control opens avenues for design of rational synergistic combinations with lunresertib
• Hyperactivation of CDK1 through inhibition of ATR or WEE1 synergistically potentiates the cytotoxic effect of lunresertib against CCNE1-high tumor cells and leads to robust tumor regressions in pre-clinical models
12:00 pm Trials & Tribulations for ATR & ATM Inhibitor Combination Trials
Synopsis
• Assess the optimal combinations within the DDR class, or with immunotherapy or cytotoxic agents
• Address the challenges of overlapping toxicity with ATR and ATM inhibitor combinations
• Evaluate dose and schedule optimization to enhance combination benefit and minimise risks
12:30 pm Journey of a DDR Patient Sample: De-risking Preclinical and Clinical Research
Synopsis
- Advanced CTC isolation with Parsortix® FDA-510k cleared capture technology
- Integration of CTCs with known DDR biomarker assays
- Provide strategies to minimize risks in the development of targeted DDR therapies
- Explore future approaches to evaluate DDR inhibitors based upon responses guided by Parsortix enriched CTCs
Removing a Piece from the DDR Puzzle: Isolating Novel Targets for Inhibition
2:00 pm Target Identification of Novel DDR Sensors
Synopsis
• Overcoming limited information to elucidate structural and functional characteristics of novel classes
• Validating molecules upstream of DDR pathways
• Anticipating and addressing potential resistance mechanisms for novel classes
2:30 pm Debating if Molecular Glues Will Stick as the Next Modality for DDR Inhibition to Improve Therapeutic Window
Synopsis
- Disrupt small molecule approaches for DDR inhibition
- Molecular glues as a growing novel modality in oncology and DDR inhibition
- Unlock a new era and targeting specific non-catalytic proteins in DDR pathways
3:00 pm Networking Break
Beyond PARP: Assessing Current Updates
2:00 pm Checking in on Cell Cycle Checkpoint Regulators for DDR Inhibition
Synopsis
• Analysing mechanisms of DDR inhibitor targets involved in cell cycle checkpoint regulation
• Inspect the role of WEE1 inhibitors for the treatment of PARP inhibitor-resistant cancers
• Design and clinical updates for WEE1 inhibitors
2:30 pm Unveiling DNA breaks through direct STRIDE assays for precision in pre-clinical and clinical development of DDR inhibitors.
Synopsis
- The importance of direct DNA breaks detection in investigation of MoA and PD effects of DDR inhibitor
- Introduction to STRIDE platform with examples of its applications in pre-clinical and patient-derived samples
- New quantitative, functional assays to study the status of homologous recombination repair in tumor biopsies
2:45 pm What are the Unique Selling Points of USP1 for Synthetic Lethality?
Synopsis
• Updates for novel selective USP1 inhibitors in BRCA1-deficient cells for patients who do not respond to PARP inhibitors
• Exploring updates for molecules with ADME properties and PK profiles
• Unearth data for potential monotherapy and combination therapies of USP1 inhibitors
3:15 pm Testing for Homologous Recombination Deficiency in Ovarian & Other Tumor Types
Synopsis
- Myriad developed the MyChoice CDx test to identify patients with homologous recombination deficient (HRD) tumors
- Many other HRD tests show limited agreement with the clinically validated companion diagnostic test
- MyChoice CDx is approved for ovarian cancer, but may have applications in breast and prostate cancer
1:00 pm Lunch
3:30 pm Afternoon Break
IMPROVING SAFETY & EFFICACY OF NOVEL DDR INHIBITORS
4:00 pm Investigating Pharmacology of Novel DDR Inhibitors to Support Clinical Development
Synopsis
• Implementing models and simulation to improve understanding of second and
third wave DDR inhibitors
• Determining appropriate inhibition levels within a dynamic range for subsequent
lead optimization
• Pre-clinical pharmacology lessons to mitigate haem toxicity of combination
therapies
4:30 pm Panel Discussion: What Makes the Perfect Next-Generation DDR Inhibitor Target?
Synopsis
• How does protein size and function impact small molecule approaches?
• Where does pathway redundancy fit into the journey of finding new targets?
• Why have next generation targets been less successful moving through clinical phases?
5:00 pm Chair’s Closing Remarks
5:05 pm Scientific Poster Presentation
Synopsis
This is an informal session to help you connect with your peers in a relaxed atmosphere and forge new and beneficial relationships. With an audience of DDR inhibitor enthusiasts eager to hear the latest cutting-edge advancements, you will have the opportunity to display a poster presenting your own work. Additionally, you will have the chance to review others’ posters displaying novel approaches to biomarker development, novel target discovery, and trial updates.
