All times shown are EST.
7:00 am Registration & Coffee
8:00 am Chair’s Opening Remarks
8:10 am Three Generations of DDR Therapeutics – Where Are We Now
Synopsis
• A landscape overview of the DDR Therapeutic landscape, focusing on the first generation of approved PARP inhibitors
• A detailed look at the preclinical and clinical second generation DDR assets, including; specialized PARP-targeted assets, ATR, and WEE1 inhibitors
• A review of a third generation of novel DDR targets, including POL-Theta, WRN, and PARG
PARP INHIBITION: NEXT-GEN PARPI’S, PARP RESISTANCE & THE FUTURE OF PARP INHIBITORS
8:30 am Progress in PARP1 Selective Inhibitors: AZD5305
Synopsis
- Delve into discovery, development and validation
9:00 am Inhibition of PARP7 by RBN-2397 Activates the Type I Interferon Response in Tumors Leading to Robust Antitumor Activity
Synopsis
- Explore how PARP7 negatively regulates the type 1 interferon response in cancer cells
- Delving into discovery, development, and clinical progress of its inhibiton which triggers antitumor immunity
9:30 am Panel Discussion: PARPi’s: The Whole Story? PARP & DDR Biomarkers, Targets & Hope in Indications Outside of Breast & Ovarian
Synopsis
- Sharing insights into future directions and what to anticipate as standards evolve for PARP and other DDRi’s in the clinic
- How is it looking for prostate? leukemia? GBM? pancreatic? endometrial? SCLC?
- What are the differences between cancers in terms of resistance to PARP inhibitors?
- Thoughts on moving to a more genomic rather than indication-specific biomarker-driven treatment strategy?
- Understanding the hope for the more understudied PARP’s
DEVELOPING CLINICALLY SUCCESSFUL WEE1 & ATR INHIBITORS FOR CANCER THERAPY
10:00 am Preclinical & Clinical Exploration of ATR Inhibitors
Synopsis
- Preclinical pharmacology profile of Merck ATR inhibitors (Berzosertib, M1774)
- Preclinical exploration of options for mono- and combination therapy
- Directions of clinical development for ATR inhibitors
10:30 am Speed Networking
11:20 am Progress in ATR & WEE1 Inhibitors: As Single Agents & Synergy in Combination Therapy
11:50 am A New Dimension in Precision Oncology with the SPOT-LX DNA Repair Testing Platform
Synopsis
• LXRepair develops funtional repair assays for a comprehensive characterization of major repair pathways in parallel
• Inhibitors specificity and efficacy can be rapidly investigated
• Assays can be used to stratify patients and monitor patients response to various DNA damaging drugs and DDR inhibitors
12:00 pm Discovery & Progress of ZN-c3, a Highly Potent & Selective WEE1 Inhibitor Undergoing Evaluation in Clinical Trials for the Treatment of Cancer
Synopsis
- Discovery of ZN-c3 as a potent and selective Wee1 inhibitor
- Exploring ZN-c3 antitumor effect as a single agent and in combination
- Diving into recent ZN-c3 clinical data
12:30 pm Targeting Replication Stress in Cancers with Adavosertib, the First in Class WEE1 Inhibitor
Synopsis
- Delving into WEE1 inhibitors, which have the potential for monotherapy activity in cancers with high levels of basal replication stress
- In this monotherapy scenario, in addition to the G2/M checkpoint override resulting from CDK1 deregulation, the activation of CDK2 appears to be the main driver with downregulation of RRM2 and dNTP reduction observed
- Exploring combination of adavosertib with the PARP inhibitor olaparib can overcome of PARPi resistance in both preclinical models and based on emerging data, in the clinic
1:00 pm Clinical Effectiveness of myChoice® CDx Genomic Instability as a CDx Biomarker
Synopsis
– Explore the only FDA approved HRD score CDx to prescribe PARPi’s
– Understand the use of broad biomarker offering for patient selection and therapeutic response
– Germline, somatic (myChoice HRD score, and gene panel), TMB, MSI
– Assessing gold standard myChoice HRD vs. other HRD measures
1:30 pm Lunch Break
2:20 pm Panel Discussion: A Comparison; The Challenges & Learnings of Developing ATR inhibitors – What Clinical Space Will They Occupy?
Synopsis
- Analyzing the current applications of these inhibitors both in preclinical and clinical studies either as single agents or in combinations with chemotherapy, radiotherapy and immunotherapy
- Dissecting toxicity profiles (bone marrow toxicity?)
- Opening the ATR inhibitor black box: what clinical space will they occupy?
- Understanding biomarker indications for ATR sensitivity: Cyclin E, ATM Loss? not as clear as BRCA for PARP
- What patients? What indications? What combinations do you foresee having optimal efficacy?
NOVEL METHODOLOGIES, FUNCTIONAL GENOMIC APPROACHES & IMAGING TECHNOLOGIES TO REVOLUTIONIZE PATHWAY UNDERSTANDING, COMPOUND OPTIMIZATION & CLINICAL TRANSLATION
2:50 pm Exploring the Landscape of PARP Inhibitor Selectivity in Cells with NanoBRET
Synopsis
• Introduction to NanoBRET Target Engagement: WEE1, PKMYT1, and CHK1 kinase inhibitor profiling in cells
• Development of a pan-PARP live cell target engagement system
• Revealing unexpected engagement of understudied mono-PARPs in cells
3:00 pm Screening & Best Assays for Compound Optimization: Quick SAR By X-Ray Poses
Synopsis
- Structural biology/crystal structures in DDR drug discovery
- Quick conversion of hits to leads, structure-guided optimization
- Application of the approach for novel oncology therapeutics
3:30 pm A Transcriptomic Model of Homologous Recombination Deficiency in a Real-World Pan-Cancer Cohort
Synopsis
- Gene expression can be used to accurately predict HRD-status across solid tumor cohorts
- This transcriptomic model, HRD-RNA, enriches for samples with biallelic loss in BRCA1/2 and other genes in the homologous recombination pathway
- Cohorts, outside traditional BRCA-associated cohorts, have samples with biallelic loss of BRCA1/2 and samples predicted HRD+, suggesting new avenues for HRD targeted therapies
4:00 pm Afternoon Refreshments & Networking Break
ESTABLISHING A PRE-CLINICALLY VALIDATED NOVEL TARGET: POLΘ
4:30 pm Panel Discussion: Towards Bridging the Gap with the Clinic
Synopsis
- Exploring optimal validation in clinics
- Standardizing the approach in the clinic so we can go back preclinically – which models?
- Gathering early clinical information – robust translational medicine program
- How can you best parallel with translational – ctDNA metabolomics
- Discussing mathematical modeling use potentials for dose adjustment and tolerability
- Why do the colony formation assays take so long and what are the alternatives – reliability? Taking cell proliferation rate into account
- Novel methods to translate drug potency into a cellular format?
- Understanding pharmacodynamics technology platforms and the clinical challenges in the drug discovery program for DDR targets; what target engagement assays, assays, validation, mechanistic, tissue distribution, toxicity, and colony formation assays are being used
- How do you prove target engagement – why a lack of cell viability assay usage?
5:00 pm Exploring Polθ as a New DDR Target
Synopsis
- Discovery and preclinical development of first-in-class inhibitors for oncology in a PARP-resistant setting
- Leveraging synthetic lethality and understanding of the theta-mediated end joining (TMEJ) to determine a validated target
- Latest from the lab, clinical validation, and future directions
- Discussing how it will compare to PARP
- Dissecting how to leverage it as a novel target
- Combination – who, where, what?