On June 4, 2018 Aptose Biosciences Inc. (NASDAQ:APTO) (TSX:APS) reported the publication of preclinical data elucidating the mechanism of action of APTO-253, the company’s clinical stage anticancer product candidate (Press release, Aptose Biosciences, JUN 4, 2018, View Source;p=RssLanding&cat=news&id=2352950 [SID1234527120]). The data are published in two separate articles in the June 2018 issue (Volume 17, Number 6) of Molecular Cancer Therapeutics, a peer-reviewed journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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The first publication, entitled "APTO-253 stabilizes G-quadruplex DNA, inhibits MYC expression and induces DNA damage in acute myeloid leukemia cells," demonstrates that the APTO-253 small molecule anticancer agent inhibits expression of the MYC oncogene and depletes cells of the MYC protein, triggers the DNA repair and stress response pathways, and promotes programmed cell death (apoptosis) in acute myeloid leukemia (AML) cell lines and fresh bone marrow samples derived from patients with AML and other hematologic malignancies that often depend on MYC upregulation. The data demonstrate a multifaceted mechanism of action for APTO-253, primarily through engagement of select G-quadruplex DNA structures, one of which is located in the promoter of the MYC gene and is uniquely suited to targeting hematopoietic malignancies.

MYC dysregulation is a common driver in many malignancies, making it an attractive therapeutic target. Repression of MYC expression by bromodomain (BET) inhibitors has proven effective at triggering apoptosis in leukemia cells; however, inhibition of bromodomain proteins can cause severe toxicities and myelosuppression. Unlike BET inhibitors and other cancer chemotherapies, APTO-253 acts through a distinct mechanism and does not cause toxicity to normal bone marrow cells, as demonstrated across various species, including humans. And, as a first in class MYC inhibitor that does not cause myelosuppression, APTO-253 may be particularly appropriate for management of patients having AML and other hematologic malignancies with compromised bone marrow function.

The second publication, entitled "APTO-253 is a new addition to the repertoire of drugs that can exploit DNA BRCA1/2 deficiency," expands on data from a poster presentation at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting. This study identified a synthetic lethal interaction of APTO-253 in cancer cells deficient in BRCA1 or BRCA2 function, causing these cells to be hyper-sensitive to APTO-253. The research team found that APTO-253 stabilizes certain quadruplex DNA structures, which can elicit the DNA damage repair response and exhibit synthetic lethality comparable to olaparib – an FDA-approved targeted therapy that acts against cancers in people with hereditary BRCA1 or BRCA1 mutations, including some ovarian, breast and prostate cancers, although through a different mechanism. The findings revealed for APTO-253 potential new solid tumor indications in which patients with defined mutations can be genetically identified.

"These data provide new insights into the mechanism of action of APTO-253 and add to our knowledge of how this novel agent inhibits expression of the MYC gene, an oncogene that promotes tumor growth and resistance to drugs in AML and other cancers," said William G. Rice, Ph.D., Chairman, President and Chief Executive Officer.

About APTO-253

APTO-253 is a clinical-stage small molecule targeted therapeutic agent that inhibits expression of the MYC oncogene, leading to cell cycle arrest and programmed cell death (apoptosis) in human-derived solid tumor and hematologic cancer cells, without causing general myelosuppression of the healthy bone marrow. The MYC oncogene is overexpressed in hematologic cancers, including acute myeloid leukemia (AML). Aptose researchers have reported the ability of APTO-253 to induce cell death, or apoptosis, in multiple blood cancer cell lines including AML, as well as in vitro synergy with various classes of conventional approved and investigational therapies for AML or myelodysplastic syndromes (MDS). New findings reveal that APTO-253 might also serve certain solid tumor patients with BRCA1/2 mutations, but without causing toxicity to the normal bone marrow functions.