Kura Oncology, Inc. · NASDAQ:KURA
Kura Oncology — CTOS 2024 Annual Meeting
22 slides from Kura Oncology's conference presentation, 2024
Slide 1: Menin Inhibitor Ziftomenib Synergizes with Imatinib in TKI-Resistant GIST Models
Menin Inhibitor Ziftomenib Synergizes with Imatinib in Tyrosine Kinase Inhibitor-Resistant Gastrointestinal Stromal Tumor Models Exposing the epigenetic Achilles heel of KIT-driven tumors Asako McCloskey, Quinn Reilly, Judy Wu, and Francis Burrows Kura Oncology, Inc. Content of this presentation is
Slide 2: Disclosures
Disclosures • Asako McCloskey (Presenter): Employee and stockholder of Kura Oncology, Inc.; holds patents and/or patent applications with Kura Oncology, Inc. • Quinn Reilly: Former employee and stockholder of Kura Oncology, Inc. • Judy Wu: Employee and stockholder of Kura Oncology, Inc. • Francis Bu
Slide 3: The GIST transcriptional program is involved in oncogenesis via epigenetic mechanisms
The GIST transcriptional program is involved in oncogenesis via epigenetic mechanisms Signaling pathways of KIT-mutated GIST1 • Oncogenic KIT activates the GIST transcriptional program required for tumorigenesis through transcription factors such as ETV12 GIST transcriptional program 1. Blay JY (202
Slide 4: The GIST transcriptional program is involved in oncogenesis via epigenetic mechanisms
The GIST transcriptional program is involved in oncogenesis via epigenetic mechanisms Signaling pathways of KIT-mutated GIST1 • Oncogenic KIT activates the GIST transcriptional program required for tumorigenesis through transcription factors such as ETV12 • Menin is a scaffold protein known to regul
Slide 5: The GIST transcriptional program is involved in oncogenesis via epigenetic mechanisms
The GIST transcriptional program is involved in oncogenesis via epigenetic mechanisms Signaling pathways of KIT-mutated GIST1 • Oncogenic KIT activates the GIST transcriptional program required for tumorigenesis through transcription factors such as ETV12 • Menin is a scaffold protein known to regul
Slide 6: Combination treatments manifested synergistic antitumor activity in a partially imatinib-resistant second-line GIST PDX model
Combination treatments of ziftomenib and TKIs manifested synergistic antitumor activity in a partially imatinib-resistant second-line GIST PDX model Ex11 + Ex13, KIT Ex11 del and V654A GS11331, KITGS11331 Ex11 del and V654A vehicle • Both TKI monotherapies slowed tumor 2500 growth, but neither induc
Slide 7: Combination treatments manifested synergistic antitumor activity in a partially imatinib-resistant second-line GIST PDX model
Combination treatments of ziftomenib and TKIs manifested synergistic antitumor activity in a partially imatinib-resistant second-line GIST PDX model Ex11 + Ex13, KIT Ex11 del and V654A GS11331, KITGS11331 Ex11 del and V654A vehicle • Both TKI monotherapies slowed tumor 2500 growth, but neither induc
Slide 8: Combination treatments manifested synergistic antitumor activity in a partially imatinib-resistant second-line GIST PDX model
Combination treatments of ziftomenib and TKIs manifested synergistic antitumor activity in a partially imatinib-resistant second-line GIST PDX model Ex11 + Ex13, KIT Ex11 del and V654A GS11331, KITGS11331 Ex11 del and V654A vehicle • Both TKI monotherapies slowed tumor 2500 growth, but neither induc
Slide 9: Ziftomenib and imatinib display synthetic lethal activity in fully imatinib-resistant Ex17 GIST PDX models
Ziftomenib and imatinib display synthetic lethal activity in fully imatinib-resistant Ex17 GIST PDX models GS5108, homozygous KIT/Y823D 2500 vehicle ziftomenib (1X) Mean TV (mm3) 2000 ns imatinib 1500 ns combination 1000 500 * 0 0 10 20 30 Treatment Days • Ziftomenib and imatinib were inactive in Ex
Slide 10: Ziftomenib significantly enhanced the activity of imatinib in an imatinib-sensitive first-line GIST PDX model
Ziftomenib significantly enhanced the activity of imatinib in an imatinib-sensitive first-line GIST PDX model GS11360 (KIT/Ex11 V559G) • Imatinib monotherapy was tumoristatic, but the dosing was ziftomenib-imatinib combination induced deep 1500 stopped vehicle regressions in all animals, including s
Slide 11: Ziftomenib significantly enhanced the activity of imatinib in an imatinib-sensitive first-line GIST PDX model
Ziftomenib significantly enhanced the activity of imatinib in an imatinib-sensitive first-line GIST PDX model GS11360 (KIT/Ex11 V559G) • Imatinib monotherapy was tumoristatic, but the dosing was ziftomenib-imatinib combination induced deep 1500 stopped vehicle regressions in all animals, including s
Slide 12: The ziftomenib-imatinib combination is inactive in KIT-independent GIST PDX models
The ziftomenib-imatinib combination is inactive in KIT-independent GIST PDX models ME3332 GS11338 (KIT WT) GS11341 (KIT/V559G, low-expression) 1400 dosing 4000 stopped 1500 1200 vehicle vehicle Mean TV (mm3) 1000 ziftomenib ziftomen Mean TV (mm ) Mean TV (mm3) 3 3000 800 imatinib 1000 imatinib 2000
Slide 13: A pharmacodynamic study was conducted to investigate the mechanism of action of the combination
A pharmacodynamic study was conducted to investigate the mechanism of action of the combination Ex11 + Ex13 • A western blot test was conducted to investigate KIT protein level changes and downstream oncogenic signaling • qPCR was conducted to measure KIT gene transcription Presented by: Asako McClo
Slide 14: Ziftomenib and imatinib combine to drive complete KIT protein depletion
Ziftomenib and imatinib combine to drive complete KIT protein depletion in a partially imatinib-resistant second-line GIST PDX model Ex11 + Ex13, GS11331 Day 8 vehicle zifto imatinib combo • Although imatinib increased total KIT protein Total KIT levels, the combination with ziftomenib resulted in p
Slide 15: Ziftomenib and imatinib combine to drive complete KIT protein depletion
Ziftomenib and imatinib combine to drive complete KIT protein depletion in a partially imatinib-resistant second-line GIST PDX model Ex11 + Ex13, GS11331 Day 8 vehicle zifto imatinib combo • Although imatinib increased total KIT protein Total KIT levels, the combination with ziftomenib resulted in p
Slide 16: Ziftomenib and imatinib combine to silence KIT gene transcription
Ziftomenib and imatinib combine to silence KIT gene transcription RT-qPCR Ex11 + Ex13, GS11331 Day 5 • Both imatinib and ziftomenib modestly inhibited KIT POL2RA KIT transcription, as previously reported1 1.2 Relative expression levels 1.2 Relative expression levels ns 1.0 1.0 ns ** ns 0.8 ** 0.8 0.
Slide 17: Ziftomenib and imatinib combine to silence KIT gene transcription
Ziftomenib and imatinib combine to silence KIT gene transcription RT-qPCR Ex11 + Ex13, GS11331 Day 5 • Both imatinib and ziftomenib modestly inhibited KIT POL2RA KIT transcription, as previously reported1 1.2 Relative expression levels 1.2 Relative expression levels ns 1.0 1.0 ns • Combination treat
Slide 18: Ziftomenib and imatinib combine to silence KIT gene transcription
Ziftomenib and imatinib combine to silence KIT gene transcription RT-qPCR Ex11 + Ex13, GS11331 Day 5 • Both imatinib and ziftomenib modestly inhibited KIT POL2RA KIT transcription, as previously reported1 1.2 Relative expression levels 1.2 Relative expression levels ns 1.0 1.0 ns • Combination treat
Slide 19: Ziftomenib and imatinib combine to silence KIT gene transcription
Ziftomenib and imatinib combine to silence KIT gene transcription RT-qPCR Ex11 + Ex13, GS11331 Day 5 Day 8 • Both imatinib and ziftomenib modestly inhibited KIT POL2RA KIT KIT transcription, as previously reported1 ns 1.2 Relative expression levels 1.2 1.4 Relative expression levels Relative express
Slide 20: Ziftomenib and imatinib combine to silence KIT in a mutation-independent manner
Ziftomenib (menin inhibitor) and imatinib (TKI) combine to silence KIT in a mutation-independent manner Presented by: Asako McCloskey 2024 MENIN INHIBITOR ZIFTOMENIB SYNERGIZES WITH IMATINIB IN TYROSINE Content of this presentation is the property of the author, ANNUAL MEETING KINASE INHIBITOR (TKI)
Slide 21: Summary
Summary • Ziftomenib-imatinib combination treatment unexpectedly showed robust antitumor activity not only in imatinib-sensitive but also in imatinib-resistant KIT-dependent GIST models representing the full GIST treatment continuum • The combination of ziftomenib + imatinib exerts antitumor activit
Slide 22: Acknowledgements
Acknowledgements • Translational Research team at Kura Oncology, Inc. Presented by: Asako McCloskey 2024 MENIN INHIBITOR ZIFTOMENIB SYNERGIZES WITH IMATINIB IN TYROSINE Content of this presentation is the property of the author, ANNUAL MEETING KINASE INHIBITOR (TKI)-RESISTANT GASTROINTESTINAL STROMA