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Molecular Cancer Therapeutics
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Therapeutic Agents: Other

Abstract C067: Mechanistic study of the superior anti-cancer properties of a first-in-class small molecule targeting PCNA

Long Gu, Min Li, Robert Lingeman, Robert J Hickey, Yilun Liu and Linda H Malkas
Long Gu
The Beckman Institute of City of Hope, Duarte, CA.
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Min Li
The Beckman Institute of City of Hope, Duarte, CA.
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Robert Lingeman
The Beckman Institute of City of Hope, Duarte, CA.
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Robert J Hickey
The Beckman Institute of City of Hope, Duarte, CA.
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Yilun Liu
The Beckman Institute of City of Hope, Duarte, CA.
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Linda H Malkas
The Beckman Institute of City of Hope, Duarte, CA.
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DOI: 10.1158/1535-7163.TARG-19-C067 Published December 2019
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Abstracts: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; October 26-30, 2019; Boston, MA

Abstract

Proliferating cell nuclear antigen (PCNA), through its interaction with various proteins involved in DNA synthesis, cell cycle regulation, and DNA repair, plays a central role in maintaining genome stability. We previously reported a novel cancer associated PCNA isoform (dubbed caPCNA), which was predominantly expressed in a broad range of cancer cells and tumor tissues, but not significantly in non-malignant cells. We found that the caPCNA-specific antigenic site lies between L126 and Y133, a region within the interdomain connector loop of PCNA that is known to be a major binding site for many of PCNA’s interacting proteins. A cell permeable peptide harboring the L126-Y133 sequence inhibited PCNA function in cancer cells and selectively kills cancer cells and xenograft tumors. Based on these observations, we sought small molecules targeting this peptide region of PCNA as potential broad-spectrum anti-cancer agents. Our effort led to a drug candidate, AOH1996, which selectively kills a broad range of cancer cells at high nanomolar concentrations, but is not associated with significant toxicity to non-malignant cells. It also works synergistically with DNA damaging chemotherapeutic drugs, such as cisplatin and irinotecan, to selectively kill cancer cells. This compound is orally available to animals and suppresses tumor growth in a dosage form compatible to clinical applications. Importantly, it doesn’t cause significant toxicity at 2.5 times its effective dose. Mechanistically, AOH1996 competes with T3, a known PCNA ligand, for binding to PCNA. However, the mechanism by which AOH1996 exerts its effect on cancer cells may not be identical to what have been reported for the T3 analogs. In particular, we found that AOH1996 interferes with the association of PCNA and its binding proteins, leading to DNA replication stress, blockade of homologous recombination-mediated DNA repair, and induction of apoptosis in cancer cells. These findings demonstrated the potential of this compound as a novel therapeutic agent warranting clinical investigation for cancer treatment. We have started planning a phase 1 clinical study for this compound.

Citation Format: Long Gu, Min Li, Robert Lingeman, Robert J Hickey, Yilun Liu, Linda H Malkas. Mechanistic study of the superior anti-cancer properties of a first-in-class small molecule targeting PCNA [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 C067. doi:10.1158/1535-7163.TARG-19-C067

  • ©2019 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 18 (12 Supplement)
December 2019
Volume 18, Issue 12 Supplement
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Abstract C067: Mechanistic study of the superior anti-cancer properties of a first-in-class small molecule targeting PCNA
Long Gu, Min Li, Robert Lingeman, Robert J Hickey, Yilun Liu and Linda H Malkas
Mol Cancer Ther December 1 2019 (18) (12 Supplement) C067; DOI: 10.1158/1535-7163.TARG-19-C067

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Abstract C067: Mechanistic study of the superior anti-cancer properties of a first-in-class small molecule targeting PCNA
Long Gu, Min Li, Robert Lingeman, Robert J Hickey, Yilun Liu and Linda H Malkas
Mol Cancer Ther December 1 2019 (18) (12 Supplement) C067; DOI: 10.1158/1535-7163.TARG-19-C067
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Therapeutic Agents: Other: Poster Presentations - Proffered Abstracts

  • 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: Poster Presentations - Proffered Abstracts
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Molecular Cancer Therapeutics
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