Novel phase I study combining G1 phase, S phase, and G2/M phase cell cycle inhibitors in patients with advanced malignancies

Abstract

PURPOSE:Cancer is a manifestation of aberrant cellular proliferation, and the cell cycle is one of the most successfully drugged targets in oncology. No prior study has been reported that simultaneously targets the 3 principal cell cycle phases populated by proliferating cells -G 1 , S, and G 2 /M.METHODS: Temsirolimus (G 1 inhibitor), topotecan (S inhibitor), and bortezomib (G 2 /M inhibitor) were administered in combination to patients with advanced malignancies using a 3+3 dose escalation schedule to assess the safety and establish the maximum tolerated dose (primary endpoints) of this cell cycle targeting approach. An in silico pharmacodynamic model using established effects of each of these agents on the cell cycle was used to validate the regimen and to guide the dosing regimen.RESULTS: Sixty-two subjects were enrolled. The most common adverse events and dose-limiting toxicities were cytopenias, consistent with the cell cycle targeting approach employed. All cytopenias resolved to baseline values upon holding study drug administration. The maximum tolerated dose was temsirolimus 15 mg/kg IV D1, 8, 15; topotecan 2.8 mg/m 2 IV D1, 8; and bortezomib 0.9 mg/m 2 IV D1, 4, 8, 11 of a 21-day cycle. In silico modeling suggests the regimen induces cell population shifts from G 2 /M and S phases to G 1 phase and the quiescent G 0 phase. Eighteen percent of subjects (11/62) achieved partial response (n D 2, serous ovarian and papillary thyroid) or stable disease for > 6 months (n D 9).

Absence of terminal deoxynucleotidyl transferase expression in T‐ALL/LBL accumulates chromosomal abnormalities to induce drug resistance

“…The G0 phase refers to the resting cells which are outside the cell cycle and are not affected by chemotherapy 19,20 . The G0 phase of cells does not express Ki‐67 21 .…”

“…The G0 phase refers to the resting cells which are outside the cell cycle and are not affected by chemotherapy. 19,20 The G0 phase of cells does not express Ki-67. 21 We wanted to know whether the suppression of the cell cycle after TDT knockout was associated with more G0 phase cells which finally led to drug resistance.…”

Deep response to a combination of mTOR inhibitor temsirolimus and dual immunotherapy of nivolumab/ipilimumab in poorly differentiated thyroid carcinoma with PTEN mutation: a case report and literature review

“…In a phase II trial, all patients with thyroid cancer, except one with ATC, experienced stable disease, or partial response on the combination of temsirolimus and sorafenib ( 27 ). In another phase I trial, patients with PTC and FTC remained without progression longer than a year with temsirolimus, topotecan, and bortezomib treatment ( 24 ). A recent study using patient-derived xenograft mouse models of oncocytic carcinoma of the thyroid (OCA) with upregulated mTOR signaling showed tumor suppressing effect of mTOR inhibitors for both primary tumor and metastasis ( 37 ).…”

“…A total of 7 clinical trials, three retrospectives, one case report, and one preliminary report were found through a literature search using PubMed (National Library of Medicine, Bethesda, MD, USA). In total, eight clinical trials and one retrospective study are analyzed and described in Table 1 (23)(24)(25)(26)(27)(28)(29)(30)(31). One case report and one retrospective study were excluded from the table as their patients overlapped with the clinical trials (32, 33).…”

TOP1 modulation during melanoma progression and in adaptative resistance to BRAF and MEK inhibitors

“…Here we see that TOP1 inhibition modulates different genes in parental and BRAFi/MEKi-resistant cells through our RPPA analysis. In parental cells, Topotecan modulates pathways related to proteins included in the response of DNA damage and stress, that are the known mechanisms of action for Topotecan (69)(70)(71), whereas, in BRAFi/MEKi-resistant cells, Topotecan upregulates different metabolic processes and downregulates the metalloproteinases 2 and 9 that are particularly important in the invasion process.…”