Skip to main content
  • AACR Journals
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

AACR logo

  • Register
  • Log in
  • My Cart
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • Focus on Radiation Oncology
      • Novel Combinations
      • Reviews
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

  • AACR Journals
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in
  • My Cart

Search

  • Advanced search
Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • Focus on Radiation Oncology
      • Novel Combinations
      • Reviews
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

Therapeutic Agents: Other

Abstract C064: The investigational peptide drug ALRN-6924, a dual inhibitor of MDMX and MDM2, is an effective myelopreservation agent

Luis A Carvajal, David Sutton, Mariam Mounir, Joseph McClanaghan, Vincent Guerlavais, Manuel Aivado, Vojislav Vukovic and Allen Annis
Luis A Carvajal
Aileron Therapeutics, Inc., Watertown, MA.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David Sutton
Aileron Therapeutics, Inc., Watertown, MA.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mariam Mounir
Aileron Therapeutics, Inc., Watertown, MA.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joseph McClanaghan
Aileron Therapeutics, Inc., Watertown, MA.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Vincent Guerlavais
Aileron Therapeutics, Inc., Watertown, MA.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Manuel Aivado
Aileron Therapeutics, Inc., Watertown, MA.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Vojislav Vukovic
Aileron Therapeutics, Inc., Watertown, MA.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Allen Annis
Aileron Therapeutics, Inc., Watertown, MA.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1158/1535-7163.TARG-19-C064 Published December 2019
  • Article
  • Info & Metrics
Loading
Abstracts: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; October 26-30, 2019; Boston, MA

Abstract

Aim: We investigated whether p53 activation with ALRN-6924 can prevent or reduce chemotherapy-induced hematopoietic toxicity while preserving or enhancing anti-tumor efficacy of chemotherapy in p53-mutant tumors. Materials and methods: ALRN-6924 is a clinical-stage, first-in-class, stabilized cell-permeating alpha-helical peptide that disrupts the interaction of the p53 tumor suppressor protein with its endogenous inhibitors, MDMX and MDM2. For p53 wild-type cells such as normal bone marrow, p53 activation can induce transient, dose-dependent cell cycle arrest, reducing sensitivity to chemotherapy-induced cellular toxicity. For p53-mutant cancer cells, ALRN-6924 has no effect on the cell cycle, leaving them vulnerable to chemotherapy. ALRN-6924-induced cell cycle arrest was measured by flow cytometry in human bone marrow CD34+ cells following incubation with ALRN-6924 ex vivo for 24 hours. DNA synthesis and DNA content were quantified by flow cytometry using EdU incorporation and Hoechst 33342 staining, respectively. Cell cycle arrest in the bone marrow of ALRN-6924-treated C57BL/6 mice was measured by flow cytometry using EdU incorporation in lineage negative, Kit positive hematopoietic stem and progenitor cells. Topotecan-induced DNA damage was measured in human bone marrow CD34+ cells by H2γX incorporation following exposure to vehicle or ALRN-6924 for 24 hours to induce cell cycle arrest, then incubated with topotecan for an additional 24 hours following a wash-out step. Topotecan-induced neutropenia was measured in female C57BL/6 mice following topotecan treatment on days 1-5 and either ALRN-6924 or vehicle on days 0-4. Female C57BL/6 mice bearing subcutaneous p53-mutant MC38 syngeneic tumors were treated with ALRN-6924, vehicle and topotecan on the same dosing regimen and followed until tumors reached >1000mm3. Results: ALRN-6924 induces transient, reversible cell cycle arrest in bone marrow cells in vitro and in vivo, and protects human bone marrow cells against topotecan-induced DNA damage ex vivo. In a mouse model of topotecan-induced neutropenia, ALRN-6924 protected against neutrophil depletion when daily administration started 24 hours prior to the 1st dose and 30 minutes before each subsequent dose of topotecan. ALRN-6924 does not diminish topotecan’s anti-tumor activity in the p53-mutant MC38 syngeneic mouse cancer model, with the ALRN-6924 + topotecan combination yielding modest enhancement of survival. Body weights and mortality data suggest ALRN-6924 and combinations with topotecan were tolerated at the doses tested. Conclusions: ALRN-6924 reduces chemotherapy-induced hematopoietic toxicity in healthy human bone marrow cells ex vivo and in mouse models of topotecan-induced neutropenia in vivo, while preserving or enhancing anti-tumor efficacy in p53-mutant tumors when administered intravenously prior to chemotherapy. These results support the first ALRN-6924 clinical trial for myelopreservation in topotecan-treated small-cell lung cancer patients (NCT04022876). Additional studies are underway to support ALRN-6924 as a tumor type-agnostic myelopreservation agent for cancer patients with tumors bearing p53 mutations who are treated with chemotherapy.

Citation Format: Luis A Carvajal, David Sutton, Mariam Mounir, Joseph McClanaghan, Vincent Guerlavais, Manuel Aivado, Vojislav Vukovic, Allen Annis. The investigational peptide drug ALRN-6924, a dual inhibitor of MDMX and MDM2, is an effective myelopreservation agent [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C064. doi:10.1158/1535-7163.TARG-19-C064

  • ©2019 American Association for Cancer Research.
Previous
Back to top
Molecular Cancer Therapeutics: 18 (12 Supplement)
December 2019
Volume 18, Issue 12 Supplement
  • Table of Contents

Sign up for alerts

Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Molecular Cancer Therapeutics article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Abstract C064: The investigational peptide drug ALRN-6924, a dual inhibitor of MDMX and MDM2, is an effective myelopreservation agent
(Your Name) has forwarded a page to you from Molecular Cancer Therapeutics
(Your Name) thought you would be interested in this article in Molecular Cancer Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Abstract C064: The investigational peptide drug ALRN-6924, a dual inhibitor of MDMX and MDM2, is an effective myelopreservation agent
Luis A Carvajal, David Sutton, Mariam Mounir, Joseph McClanaghan, Vincent Guerlavais, Manuel Aivado, Vojislav Vukovic and Allen Annis
Mol Cancer Ther December 1 2019 (18) (12 Supplement) C064; DOI: 10.1158/1535-7163.TARG-19-C064

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Abstract C064: The investigational peptide drug ALRN-6924, a dual inhibitor of MDMX and MDM2, is an effective myelopreservation agent
Luis A Carvajal, David Sutton, Mariam Mounir, Joseph McClanaghan, Vincent Guerlavais, Manuel Aivado, Vojislav Vukovic and Allen Annis
Mol Cancer Ther December 1 2019 (18) (12 Supplement) C064; DOI: 10.1158/1535-7163.TARG-19-C064
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
  • Info & Metrics
Advertisement

Related Articles

Cited By...

More in this TOC Section

Therapeutic Agents: Other

  • Abstract LB-C10: Preclinical synergistic anti-tumor effect against multiple cancer types by EZH2 inhibitor EPZ-6438 plus imipridone ONC201 to mimic H3K27M mutation observed in DIPG tumors that respond to ONC201 in the clinic
  • Abstract C069: The identification of MRTX849, a novel KRASG12C inhibitor under clinical investigation, provides insight toward therapeutic susceptibility of KRAS mutant cancers
  • Abstract C070: CLR 180099, a lipid raft targeted phospholipid-drug conjugate, shows potent improved safety and efficacy against colorectal tumors
Show more Therapeutic Agents: Other

Therapeutic Agents: Other: Poster Presentations - Proffered Abstracts

  • Abstract LB-C09: The KRASG12C inhibitor MRTX849 reconditions the tumor immune microenvironment and leads to durable complete responses in combination with anti-PD-1 therapy in a syngeneic mouse model
  • Abstract C067: Mechanistic study of the superior anti-cancer properties of a first-in-class small molecule targeting PCNA
  • Abstract LB-C10: Preclinical synergistic anti-tumor effect against multiple cancer types by EZH2 inhibitor EPZ-6438 plus imipridone ONC201 to mimic H3K27M mutation observed in DIPG tumors that respond to ONC201 in the clinic
Show more Therapeutic Agents: Other: Poster Presentations - Proffered Abstracts
  • Home
  • Alerts
  • Feedback
  • Privacy Policy
Facebook  Twitter  LinkedIn  YouTube  RSS

Articles

  • Online First
  • Current Issue
  • Past Issues
  • Meeting Abstracts

Info for

  • Authors
  • Subscribers
  • Advertisers
  • Librarians

About MCT

  • About the Journal
  • Editorial Board
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2021 by the American Association for Cancer Research.

Molecular Cancer Therapeutics
eISSN: 1538-8514
ISSN: 1535-7163

Advertisement