8.00 am Morning Coffee & Registration

Morning Plenary: Late-Breaking Case-Studies

8:50 am Chair’s Opening Remarks

9:00 am Opening Address: Critical Updates from the RAS Community

  • Frank McCormick Professor (UCSF)/ Leader, NCI Ras Initiative, University of Califorina, San Francisco

9:30 am Targeting RAS(ON) Beyond KRAS G12C

Synopsis

  • Targeting RAS(ON) v first generation RAS(OFF) inhibitors
  • Drugging RAS beyond G12C
  • Targeted and rational combinations

10:00 am Pre-Clinical Development of Mutant KRAS-Specific T Cell Receptor-Engineered CD4+ & CD8+ T Cell Therapies

  • Loic Vincent Chief Scientific Officer, Affini-T Therapeutics

Synopsis

  • Advantages of TCR-engineered CD4+ and CD8+ T cell therapies to induce deep and durable anti-tumor responses against KRas mutant tumors
  • Preclinical data of TCR-engineered T cell therapies targeting KRas mutant tumors
  • Synthetic biology strategy for boosting TCR-engineered T cell trafficking and persistence in the hostile TME of KRas mutant tumors to ensure durable responses

10:30 am The Novel, Next-Generation Class I-Selective HDAC Inhibitor OKI-179 shows Chemical Synthetic Lethality & Induces Regressions in combination with RAS-Pathway Inhibitors in Multiple RAS-Pathway-Mutated Cancers

Synopsis

  • The Class I-targeting HDAC inhibitor OKI-179 shows a chemical-synthetic lethality with RAS Pathway inhibitors, inducing cell killing in RAS-pathway-mutated cells as a result of inducing unrepaired dsDNA breaks
  • OKI-179 combined with a RAS pathway inhibitor induces regressions in vivo, when the single-agent drugs alone are not effective, including tumour types with currently un-targetable RAS pathway mutations
  • Synergy is observed across multiple RAS-pathway mutations and multiple tumour types, suggesting that HDAC inhibition may be broadly applied as a backbone therapy across RAS Pathway-mutated cancers

11:00 am Broader Detection of RAS Mutations by GeneStrat NGS™ Test & their Association with Other Prognostic Markers

  • Trevor Pitcher Senior Director - Medical Affairs, Information & Publications, Biodesix Inc

Synopsis

  • High concordance between GeneStrat® targeted (ddPCR) and GeneStrat NGS™ test measuring KRAS in blood
  • Real-world detection of RAS variants in patients with NSCLC
  • Relationship between a proteomic host immune classifier and tumor mutations in the RAS pathway 

11.30 am Morning Break & Networking

Track A: Accelerating Discovery & Emerging Strategies

Discussing Successes & Challenges in Degradation Approaches

12:30 pm Targeting KRAS Mutant Solid Tumors with Novel SOS1 Bifunctional Degraders

Synopsis

  • Using our PRODEGY platform, we have designed bifunctional degraders of SOS1 – the guanine exchange factor catalysing the exchange of GDP to GTP in KRAS – as a mutation agnostic strategy to target KRAS mutant solid tumors
  • BioTheryX’s novel SOS1 bifunctional degraders rapidly and potently degrade SOS1 in a Cereblon mediated proteasomal event
  • As a function of SOS1 degradation, these small molecule bifunctional degraders also potently inhibit cell viability of a range of mutant KRAS tumor cell lines including those harboring G12V, G12C and G13D mutations, thereby emerging as a potential first-in-class therapy for cancer patients

1:00 pm Beyond KRAS: A Novel Constitutively-Active Pan-RAS Degrader

Synopsis

  • Selectively targets constitutively active forms of RAS mutants
  • Robust against mutation and overexpression resistance mechanisms
  • Able to target all RAS isoforms

Track B: Optimizing Translation & Pre-Clinical Development

Optimizing Animal Models to Improve Translation to Patient

12:30 pm Targeting Validated Oncogenic Drivers to Improve Outcomes: Kinnate’s Approach to NRASMUT Melanoma

  • Robert Pelham Vice President, Translational Medicine,, Kinnate Biopharma Inc.

Synopsis

  • Kinase inhibition for cancers with no approved targeted therapy
  • Role of CRAF inhibition in NRAS-mutant melanoma
  • Translating the approach: pre-clinical validation of KIN-2787

1:00 pm Current Progress in Defining New Vulnerabilities in RAS That Can Be Exploited to Therapeutically Inhibit KRAS-Mutant Cancers

  • John O’Bryan Professor - Cell, Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina

Synopsis

  • A new approach to inhibit the oncogenic KRAS by selectively targeting the nucleotide-free (apo) state of the protein
  • Isolation of a monobody termed R15 that selectively binds apo RAS in vitro. When expressed in cells, R15 binds and inhibits oncogenic KRAS mutants with elevated spontaneous nucleotide release rates
  • Contrary to conventional wisdom, it is possible to inhibit oncogenic KRAS by targeting the nucleotide state of the protein. Fidings provide a potential new approach to develop pharmacological inhibitors that target >50% of the oncogenic RAS proteins found in human tumors

Track C: Advancing Clinical Trials & Development

Clinical Updates from Leading Biopharma

12:30 pm Clinical Activity Demonstrated for Polyvalent Mutant KRAS Cancer Vaccine

Synopsis

  • Robust immune responses and clinical benefit observed in pancreatic cancer
  • Product and treatment scheduling strategies to enhance KRAS immune responses
  • Future development plans and IO combination options to maximize benefit

1:00 pm KRAS G12C Targeting in Chinese patients

Synopsis

  •  Safety and efficacy of KRAS G12C inhibitor JAB-21822 in Chinese patients

1.30 pm Lunch Break & Networking

Understanding the RAS Interactome & Membrane Complexities

2:30 pm Membrane Composition & RAF [CRD]-Membrane Attachment are Driving Forces for KRAS4B Dimer Stability

Synopsis

  • We performed all-atom molecular dynamics simulations of the KRAS4BGTP wild-type homodimer in the presence and absence of Raf [RBD/CRD] effectors on two model anionic lipid membranes
  • The stability of the KRAS4B homodimer is enhanced on the membrane containing a high concentration of anionic lipids in the absence of Raf effectors
  • This enhanced stability is also observed in the presence of Raf [RBD/CRD] effectors although it is not influenced by the concentration of anionic lipids in the membrane, but rather on the ability of Raf [CRD] to anchor to the membrane

3:00 pm Targeting the RAS Pathway with Chemical Switches and Molecular Glues

  • Arvin Dar Professor, Icahn School of Medicine at Mount Sinai

Synopsis

  • RAS signalling through effector pathways
  • Small molecule tools and therapeutic leads
  • Target validation

3:30 pm Interrogating the RAS Interactome for New Therapeutic Opportunities

Synopsis

  • Combining proximity labelling with CRISPR/Cas9 loss-of-function screening identified the interactomes of each RAS isoform
  • Mining these datasets for isoform-specific interactions identified PIP5K1A as specifically binding to and promoting oncogenic KRAS, but not NRAS or HRAS signalling and transformation, providing a new therapeutic opportunity
  • Mining these datasets for the top dependency identified EFR3A as a new RAS effector that recruits PI4KA to RAS in a positive feed-back loop that can be targeted to augment the anti-neoplastic activity of a G12C RAS inhibitor

4:00 pm Structure of the SHOC2-MRAS-PP1C Complex Provides New Insights into RAF Activation & Drug Development Against RAS-Driven Cancers

  • Dhirendra Simanshu Principal Scientist - Structural Biology, RAS Initiative & Group Lead, Frederick National Laboratory for Cancer Research

Synopsis

  • Dephosphorylation of a specific phosphoserine on RAF kinases by a heterotrimeric SMP complex formed by SHOC2, MRAS, and PP1C provides critical activating input
  • The Heterotrimeric SMP complex is a therapeutic target for ERK pathway inhibition in RAS-driven cancers
  • Our work provides structural insights into the role of the heterotrimeric complex in RAF activation and new avenues for therapeutic interventions

Advanced Resistance Modelling for Anti-RAS Drugs

2:30 pm Epigenetic Approaches to Modulate the RAS Pathway

  • Ana Limon Senior Vice President- Clinical Development & Medical Affairs, Oryzon Genomics

Synopsis

  • The development of kinase inhibitor resistance through epigenetic adaptation is mediated by the persistence of a small population of cells that overcome initial drug exposure
  • By selectively targeting the epigenetic mechanisms of cell survival during the early stages of drug response, durable responses to kinase inhibitors may be obtained by preventing the outgrowth of drug-resistant clones
  • Epigenetics mechanisms are able to rewire kinase signaling in several tumor models in a way that broadly suppressed the activity of other kinases and feedback loops in the RTK-RAS-MEK and Pi3K pathways

3:00 pm Initial Monotherapy Results of a Phase 1 First‑in‑Human Study of ULK1/2 Inhibitor DCC‑3116 Alone & In Combination with MAPK Pathway Inhibition

  • Frederic Reu Vice President - Early Clinical Development, Deciphera Pharmaceuticals

Synopsis

  • Mitogen-activated protein kinase (MAPK) pathway inhibition activates Unc-51–like autophagy activated kinase (ULK) 1/2 and initiates autophagy to promote survival of RAS/RAF mutant cancers
  • The first-in-class ULK1/2 inhibitor DCC-3116 is being evaluated in a phase 1, multicenter, open-label, first in-human study alone and in combination with MAPK pathway inhibition in patients with MAPK pathway mutant locally advanced or metastatic solid cancers
  • Data from the ongoing monotherapy dose escalation will be presented

3:30 pm Multi-Omics Data Integration Reveals New Targets In RAS-Mutant Cancers Resistant to KRASG12C Inhibition

Synopsis

  • In Vivo CRIPSR screens in RAS mutant cell lines models reveal new vulnerabilities for ERK/MAPK addicted cancers
  • KRASG12Ci Resistant cell lines models can be leveraged to reveal treatment emergent vulnerabilities in these cancers
  • Co-Targeting of the RAS and Hippo pathway might provide a rationale therapeutic approach to overcome resistance to RAS targeted therapies with Biomarker opportunities discussed

4:00 pm Translation Regulation of KRAS mRNA as a Unique Mutation Agnostic Approach

  • Kevin Pong Chief Business Officer, Anima Biotech

Synopsis

  • Cancer biology: KRAS mRNA dysregulation as a driver for tumorigenesis
  • Discovery platform: Screening for small molecules modulating mutant KRAS mRNA translation
  • Anima’s KRAS mRNA translation modulators target the increased translation efficiency of mutant KRAS in tumor cells

Reviewing Biomarkers of Response, Patient Considerations & Clinical Opportunities

2:30 pm Clinical Update on RAS Targeting In CRC

Synopsis

  • Multiple clinical trials are ongoing in CRC to explore the efficacy of RAS targeting, with varying degrees of effica
  • Mechanisms of adaptive resistance are prevalent, and preclinical studies can guide rational combinations
  • Based on experience to date, combinations will be needed in most settings for CRC patients

3:00 pm Rethinking KRAS: From Emerging to Actionable Biomarker In NSCLC

  • Joshua Kapp Senior Medical Scientist - Global Medical Oncology, Amgen Inc.

Synopsis

  • Challenges & opportunities associated with KRAS testing: the current state of biomarker testing in NSCLC
  • Future considerations: keeping up with the evolving complexity of RAS therapy related biomarkers

3:30 pm Mechanisms of Response & Resistance to RAS Inhibition

  • Andrew Aguirre Physician Scientist & Medical Oncologist, Dana-Farber Cancer Institute

Synopsis

  • Describe mechanisms of resistance to KRAS inhibition
  • Define potential biomarkers of response and resistance
  • Identify clinical opportunities for RAS inhibition in cancer

4:00 pm Patient Identification Strategy: Commercial Challenges & Key Considerations

Synopsis

  • Finding needle in a haystack
  • Accelerate patient identification for targeted therapies
  • Targeting the driver first

4.30 pm Afternoon Break

5:00 pm Panel Discussion: Now We Have Successfully Targeted RAS G12C, What’s Next?

Synopsis

As we close out two days dedicated to critical updates and project successes from across this community, this panel will dive into a discussion considering what is next for therapeutics targeting RAS-mutant cancers. After 40 years of dedicated science and significant progress, it is critical we expand the landscape of RAS targeted therapies beyond G12C and consider where this hugely promising therapeutic can see its next success

6.00 pm Chair’s Closing Remarks & End of the 4th Annual RAS- Targeted Drug Development Summit