Phase I clinical trial of XK469 in patients with chemo-refractory solid tumors

Alousi, Amin M.; Parchment, Ralph E.; Boinpally, Ramesh; Gadgeel, S.; Weigand, Robert T.; McCormick, Julie; LoRusso, P.

doi:10.1200/jco.2004.22.90140.2020

Cited by 3 publications

(2 citation statements)

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“…Huang et al suggested that XK469 blocked the division of colorectal cancer cells due to the reduction in GAS2 expression [11]. Additionally, the efficacy of XK469 has been validated in vivo [13] and progressed to Phase I clinical trials [12]. Although limiting toxicity was observed in clinical trials, we proposed that a synergistic combination with IM would mitigate adverse effects through reducing the required individual drug dose while maintaining the same desirable anti-leukemic effect.…”

Section: Discussionmentioning

confidence: 92%

“…The phenoxypropionic acid derivative 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy} propionic acid (XK469), a topoisomerase IIβ inhibitor, has been reported to influence GAS2 expression in colorectal cancer [11]. Moreover, XK469 has been tested in human clinical trials for solid tumors [12,13] and refractory acute leukemia [14]; therefore, its previous safe use in humans means it could be potentially repurposed to target GAS2 in CML.…”

Section: Introductionmentioning

confidence: 99%

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GAS2 Upregulation Is a Targetable Vulnerability in Chronic Myeloid Leukemia

Ramirez-Guzman,

Huang,

Cole

et al. 2024

IJTM

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Tyrosine kinase inhibitors (TKIs), such as imatinib (IM), increase the survival of chronic myeloid leukemia (CML) patients but do not eradicate the disease as leukemia stem cells (LSCs) with primitive and quiescent signatures persist after TKI monotherapy, driving disease relapse. Using single-cell publicly available transcriptomic data, we investigated potentially tractable vulnerabilities in this persistent CML LSC population. GAS2 is significantly upregulated when comparing LSCs from CML patients in remission to normal hematopoietic stem cells (HSCs). A topoisomerase IIβ inhibitor, XK469, was proposed to be repurposed as a candidate small-molecule inhibitor of GAS2, and its effect was investigated in cell line models in combination with IM in vitro. Alone, XK469 could induce cell cycle arrest/differentiation in CML cells and reduce cell viability. In combination with IM, XK469 significantly increased CML cell apoptosis and reduced CML cell clonogenic capacity. These results suggest that GAS2 is a targetable vulnerability in CML LSCs and that using XK469 in combination with TKI potentiates the sensitivity of CML cells to IM.

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Section: Discussionmentioning

confidence: 92%