Kronos Bio Highlights Data at AACR Ovarian Cancer Research Symposium that Supports Clinical Evaluation of Istisociclib in Advanced Ovarian Cancer
Kronos Bio (NASDAQ: KRON) presented new preclinical data on istisociclib (KB-0742), a CDK9 inhibitor, at the AACR Ovarian Cancer Research Symposium. The data supports the clinical evaluation of istisociclib in advanced ovarian cancer, particularly in platinum and PARP-inhibitor resistant cases.
Key findings include:
- Istisociclib triggered cell death in preclinical ovarian cancer models resistant to platinum and PARP inhibitors
- New PK/PD results show sustained downregulation of CDK9-dependent genes in PBMCs with an 80mg dose on a 4 days on/3 days off schedule
- Preclinical evidence suggests istisociclib induces DNA damage and subsequent cell death
- Istisociclib disrupted homologous recombination DNA damage repair, creating a "BRCAness" phenotype in resistant cells
Kronos Bio is currently evaluating istisociclib in a Phase 1/2 clinical trial expansion cohort for platinum-resistant high-grade serous ovarian cancer (HGSOC).
Kronos Bio (NASDAQ: KRON) ha presentato nuovi dati preclinici su istisociclib (KB-0742), un inibitore della CDK9, al Simposio di Ricerca sul Cancro Ovarico AACR. I dati sostengono la valutazione clinica di istisociclib nel cancro ovarico avanzato, in particolare nei casi resistenti al platino e agli inibitori PARP.
I principali risultati includono:
- Istisociclib ha indotto la morte cellulare in modelli preclinici di cancro ovarico resistenti ai composti a base di platino e agli inibitori PARP
- I nuovi risultati di PK/PD mostrano una downregolazione sostenuta dei geni dipendenti da CDK9 nei PBMC con una dose di 80mg seguita da un programma di 4 giorni di trattamento e 3 giorni di pausa
- Le evidenze precliniche suggeriscono che istisociclib induce danno al DNA e successiva morte cellulare
- Istisociclib ha interrotto la riparazione dei danni al DNA da ricombinazione omologa, creando un fenotipo di
Kronos Bio (NASDAQ: KRON) presentó nuevos datos preclínicos sobre istisociclib (KB-0742), un inhibidor de CDK9, en el Simposio de Investigación sobre Cáncer de Ovario de la AACR. Los datos respaldan la evaluación clínica de istisociclib en cáncer de ovario avanzado, particularmente en casos resistentes al platino y a los inhibidores de PARP.
Los hallazgos clave incluyen:
- Istisociclib provocó la muerte celular en modelos preclínicos de cáncer de ovario resistentes al platino y a los inhibidores de PARP
- Nuevos resultados de PK/PD muestran una regulación a la baja sostenida de los genes dependientes de CDK9 en PBMCs con una dosis de 80mg en un horario de 4 días de tratamiento y 3 días de descanso
- Las pruebas preclínicas sugieren que istisociclib induce daño en el ADN y posterior muerte celular
- Istisociclib interrumpió la reparación de daño en el ADN por recombinación homóloga, creando un fenotipo de
Kronos Bio (NASDAQ: KRON)는 AACR 난소암 연구 심포지엄에서 CDK9 억제제인 istisociclib (KB-0742)의 새로운 비임상 데이터를 발표했습니다. 해당 데이터는 진행성 난소암에서 특히 백금 및 PARP 억제제 저항성 사례에서 istisociclib의 임상 평가를 지원합니다.
주요 발견 사항은 다음과 같습니다:
- Istisociclib는 백금 및 PARP 억제제에 저항성을 보이는 비임상 난소암 모델에서 세포 사멸을 유도했습니다.
- 새로운 PK/PD 결과는 4일 복용/3일 휴식 스케줄에서 80mg 용량으로 PBMC에서 CDK9 의존 유전자의 지속적인 하향 조절을 보여줍니다.
- 비임상 증거는 istisociclib가 DNA 손상과 이후의 세포 사멸을 유도한다는 것을 시사합니다.
- Istisociclib는 동원체 재조합 DNA 손상 수리를 방해하여 저항성 세포에서 'BRCAness' 표현형을 생성했습니다.
Kronos Bio는 현재 백금 저항성 고등급 장액성 난소암(HGSOC) 치료를 위한 1/2상 임상 시험 확장 집단에서 istisociclib를 평가하고 있습니다.
Kronos Bio (NASDAQ: KRON) a présenté de nouvelles données précliniques sur l'istisociclib (KB-0742), un inhibiteur de CDK9, lors du Symposium sur la recherche sur le cancer de l'ovaire de l'AACR. Ces données soutiennent l'évaluation clinique de l'istisociclib dans le cancer de l'ovaire avancé, en particulier dans les cas résistants au platine et aux inhibiteurs de PARP.
Les résultats clés incluent:
- L'istisociclib a provoqué la mort cellulaire dans des modèles précliniques de cancer de l'ovaire résistants au platine et aux inhibiteurs de PARP
- De nouveaux résultats PK/PD montrent une down-régulation soutenue des gènes dépendants de CDK9 dans les PBMC avec une dose de 80 mg selon un schéma de 4 jours de traitement sur 3 jours de repos
- Des preuves précliniques suggèrent que l'istisociclib induit des dommages à l'ADN et la mort cellulaire subséquente
- L'istisociclib a perturbé la réparation des dommages à l'ADN par recombinaison homologue, créant un phénotype de
Kronos Bio (NASDAQ: KRON) hat auf dem AACR-Symposium zur Erforschung von Ovarialkrebs neue präklinische Daten zu istisociclib (KB-0742), einem CDK9-Inhibitor, vorgestellt. Die Daten unterstützen die klinische Evaluierung von istisociclib bei fortgeschrittenem Ovarialkarzinom, insbesondere in Fällen, die gegen Platin und PARP-Inhibitoren resistent sind.
Die wichtigsten Ergebnisse umfassen:
- Istisociclib hat den Zelltod in präklinischen Ovarialkarzinom-Modellen ausgelöst, die resistent gegen Platin und PARP-Inhibitoren sind
- Neue PK/PD-Ergebnisse zeigen eine anhaltende Herunterregulierung von CDK9-abhängigen Genen in PBMCs bei einer Dosis von 80 mg in einem Zeitplan von 4 Tagen Behandlung und 3 Tagen Pause
- Präklinische Beweise deuten darauf hin, dass istisociclib DNA-Schäden und den anschließenden Zelltod induziert
- Istisociclib störte die homologe Rekombination der DNA-Schadenreparatur und erzeugte einen
- Preclinical data shows istisociclib's effectiveness against platinum and PARP-inhibitor resistant ovarian cancer models
- PK/PD results demonstrate sustained downregulation of CDK9-dependent genes with the current dosing schedule
- Clinical exposures of istisociclib are consistent with efficacious levels observed in preclinical models
- Ongoing Phase 1/2 clinical trial expansion in platinum-resistant high-grade serous ovarian cancer
- None.
– New data show istisociclib (KB-0742) triggered cell death in preclinical ovarian cancer models of platinum and PARP-inhibitor (PARPi) resistance –
– New PK/PD results demonstrate that istisociclib given at 80mg on a 4 days on/3 days off schedule resulted in sustained downregulation of CDK9-dependent genes in peripheral blood mononuclear cells (PBMCs) –
SAN MATEO, Calif. and CAMBRIDGE, Mass., Sept. 23, 2024 (GLOBE NEWSWIRE) -- Kronos Bio, Inc. (Nasdaq: KRON), a company dedicated to developing small molecule therapeutics that address cancers and other diseases driven by deregulated transcription, today highlighted new preclinical data from a study of istisociclib (KB-0742). The poster presentation took place over the weekend at the American Association for Cancer Research (AACR) 15th Biennial Ovarian Cancer Research Symposium.
Kronos Bio is currently evaluating istisociclib, a CDK9 inhibitor, in an expansion cohort of a Phase 1/2 clinical trial to explore single agent activity in platinum-resistant high-grade serous ovarian cancer (HGSOC).
"We’ve demonstrated preclinical evidence that istisociclib induced DNA damage and subsequent cell death, which further supports our clinical program focused on platinum-resistant high-grade serous ovarian cancer," said Luis A. Carvajal, Ph.D., Director of Translational Development at Kronos Bio, the lead author on the poster. "Importantly, platinum or PARPi insensitive cell lines showed greater sensitivity to istisociclib in cell viability assays. Moreover, ovarian cancer cells with PARPi resistance were sensitized to PARP inhibition in the presence of istisociclib.”
Dr. Carvajal added, “Based on new PK data from our ongoing clinical trial, we conclude that plasma levels were consistent with efficacious exposures observed in preclinical models of ovarian cancer, and we are excited to be enrolling patients into an expansion cohort of patients with platinum-resistant high-grade serous ovarian cancer.”
From the presentation, “Preclinical and clinical data support clinical expansion of istisociclib (KB-0742), an oral CDK9 inhibitor, into platinum-resistant ovarian cancer,” a summary of results is outlined below.
- In vitro data demonstrate that istisociclib induced apoptosis/cell death
- Istisociclib resulted in the accumulation of γH2AX, a sensitive molecular marker of DNA damage
- Istisociclib disrupted homologous recombination (HR) DNA damage repair by downregulating BRCA1 and RAD51 creating a “BRCAness” phenotype in platinum and PARP resistant HR-proficient ovarian cancer cells
From the dose escalation portion of the Company's ongoing Phase 1/2 trial of istisociclib in relapsed or refractory transcriptionally addicted advanced solid tumors, new pharmacokinetic/pharmacodynamic (PK/PD) results were presented. From the dose and schedule optimization portion of the trial evaluating 60mg and 80mg of istisociclib administered once daily on a 4 days on/3 days off schedule:
- Clinical exposures resulted in a long half-life of approximately 24 hours, and increased and prolonged weekly exposures consistent with efficacious levels observed in preclinical models
- Concurrent with increased and prolonged istisociclib exposure, deeper and more sustained downregulation of CDK9-dependent genes was observed in peripheral blood mononuclear cells (PBMCs)
The poster from the presentation is available under the Science & Pipeline section of the Kronos Bio website.
About Kronos Bio
Kronos Bio, Inc. (Nasdaq: KRON) is a clinical-stage company dedicated to developing small molecule therapeutics that address deregulated transcription, a hallmark of cancer and other diseases. Our proprietary discovery engine decodes complex transcription factor regulatory networks to identify druggable cofactors. We screen for and optimize small molecules that target these cofactors in a tumor-specific context. These efforts have yielded a preclinical pipeline along with two internally developed drug candidates. Istisociclib (KB-0742) targets CDK9 to address MYC deregulation in solid tumors and KB-9558 targets p300 to address IRF4 dependence in multiple myeloma.
Kronos Bio is based in San Mateo, Calif., and has a research facility in Cambridge, Mass.
For more information, visit https://www.kronosbio.com or follow the Company on LinkedIn.
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