Dual Targeting of CDK and Tropomyosin Receptor Kinase Families by the Oral Inhibitor PHA-848125, an Agent with Broad-Spectrum Antitumor Efficacy

Albanese, Clara; Alzani, Rachele; Amboldi, Nadia; Avanzi, Nilla; Ballinari, Dario; Brasca, Maria Gabriella; Festuccia, Claudio; Fiorentini, Francesco; Locatelli, Giuseppe; Pastori, Wilma; Patton, Veronica; Roletto, Fulvia; Colotta, Francesco; Galvani, Arturo; Isacchi, Antonella; Moll, Jürgen; Pesenti, Enrico; Mercurio, Ciro; Ciomei, Marina

doi:10.1158/1535-7163.mct-10-0190

Cited by 52 publications

(40 citation statements)

References 49 publications

(61 reference statements)

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“…Inhibited tumour growth of ovarian cancer 287 and glioma xenografts 288 , KRAS G12D -induced lung cancer 289 and DMBA-induced mammary cancer 290 ; extended survival of mice bearing leukaemia 290 and intracranial glioma xenografts 288 …”

Section: Figurementioning

confidence: 99%

Cell cycle proteins as promising targets in cancer therapy

2017

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Preface Cancer is characterized by uncontrolled proliferation resulting from aberrant activity of various cell cycle proteins; therefore, cell cycle regulators are considered attractive targets in cancer therapy. Intriguingly, animal models demonstrated that some of these proteins are not essential for proliferation of non-transformed cells and development of most tissues. In contrast, many cancers are uniquely dependent on these proteins and are hence selectively sensitive to their inhibition. After decades of research on the physiological functions of cell cycle proteins and their relevance for cancer, this knowledge recently translated into the first approved cancer therapeutic targeting of a direct regulator of the cell cycle. Here, we review the role of cell cycle proteins in cancer, the rationale for targeting them in cancer treatment and results of clinical trials, as well as future therapeutic potential of various inhibitors. We focus only on proteins that directly regulate cell cycle progression. Cyclin-dependent kinases with transcriptional functions, as well as PARP inhibitors, which are highly successful in targeting BRCA1/BRCA2-mutant tumours, are not covered by this review.

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Section: Figurementioning

confidence: 99%

Cell cycle proteins as promising targets in cancer therapy

2017

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“…Several low molecular weight inhibitors of CDKs with various inhibitor profiles on the panel of CDKs (9)(10)(11), some with additional non-CDK targets (12,13), have entered clinical trials (for recent review see ref.…”

Section: Introductionmentioning

confidence: 99%

BAY 1000394, a Novel Cyclin-Dependent Kinase Inhibitor, with Potent Antitumor Activity in Mono- and in Combination Treatment upon Oral Application

Siemeister

Lücking

Wengner

et al. 2012

Molecular Cancer Therapeutics

130

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Deregulated activity of cyclin-dependent kinases (CDK) results in loss of cell-cycle checkpoint function and increased expression of antiapoptotic proteins, which has been directly linked to the molecular pathology of cancer. BAY 1000394 inhibits the activity of cell-cycle CDKs CDK1, CDK2, CDK3, CDK4, and of transcriptional CDKs CDK7 and CDK9 with IC 50 values in the range between 5 and 25 nmol/L. Cell proliferation was inhibited at low nanomolar concentration in a broad spectrum of human cancer cell lines. In cell-based assays, the inhibition of phosphorylation of the CDK substrates retinoblastoma protein, nucleophosmin, and RNA polymerase II was shown. Cell-cycle profiles were consistent with inhibition of CDK 1, 2, and 4 as shown in cell-cycle block and release experiments. The physicochemical and pharmacokinetic properties of BAY 1000394 facilitate rapid absorption and moderate oral bioavailability. The compound potently inhibits growth of various human tumor xenografts on athymic mice including models of chemotherapy resistance upon oral dosing. Furthermore, BAY 1000394 shows more than additive efficacy when combined with cisplatin and etoposide. These results suggest that BAY 1000394 is a potent pan-CDK inhibitor and a novel oral cytotoxic agent currently in phase I clinical trials.

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“…The results of this study [25] indicate that cell-cycle related markers (Cyclin A, Cyclin B, phospho Rb and Ki67 investigated by IHC and/or qRT-PCR) were affected in a dose-dependent manner, with a strong modulation in all patients at the recommended Phase II dose of 54 mg/m 2 /day.…”

Section: Resultsmentioning

confidence: 99%

“…PHA-848125AC is an oral, potent dual TRKA inhibitor and multi-CDK inhibitor [21, 25]. The safety and efficacy profile of PHA-848125AC differentiates it from other TRKA inhibitors and CDKi tested in the clinic.…”

Section: Discussionmentioning

confidence: 99%

Phase I study of the safety, tolerability and pharmacokinetics of PHA-848125AC, a dual tropomyosin receptor kinase A and cyclin-dependent kinase inhibitor, in patients with advanced solid malignancies

et al. 2011

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Summary Purpose This phase I trial assessed the safety, maximally tolerated dose (MTD) and pharmacokinetics of TRKA/CDK inhibitor PHA-848125AC in adult patients with advanced/metastatic solid tumors. Patients and methods Patients with relapsed or refractory solid tumors, for which no standard therapy existed, were eligible. PHA-848125AC was administered orally in two schedules: daily for 7 consecutive days in 2-week cycles (i.e. 7 days on/7 days off q2wks; S1) or daily for 4 consecutive days a week for 3 weeks in 4-week cycles (i.e. 4 days on/3 days off × 3wks q4wks; S2). Result Thirty-seven patients were treated in this study, 22 in S1 and 15 in S2. The recommended phase II dose (RP2D) was 150 mg/day for either schedule. The dose-limiting toxicities (DLTs) in S1 included ataxia (Grade 2–4) and tremors (Grade 2–3). In S2, DLTs included tremors (Grade 2–3), elevated lipase (Grade 3), increased creatinine (Grade 2), and nausea and vomiting (Grade 3). These events were all reversible. In S2, out of 14 patients evaluable for efficacy, 2 patients with thymic carcinoma, showed partial response and stable disease was observed in 3 patients. Stable disease was observed in 6 out 14 patients evaluable for efficacy on S1. Drug pharmacokinetics demonstrated a half-life of approximately 33 h, and dose-proportionality with accumulation by a factor of 3 after repeated administrations. Conclusion The RP2D of PHA-848125AC was 150 mg/day on both schedules. Based on the responses noted in thymic carcinoma, a phase II study for patients with that disease is currently enrolling.

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Dual Targeting of CDK and Tropomyosin Receptor Kinase Families by the Oral Inhibitor PHA-848125, an Agent with Broad-Spectrum Antitumor Efficacy

Cited by 52 publications

References 49 publications

Cell cycle proteins as promising targets in cancer therapy

Cell cycle proteins as promising targets in cancer therapy

BAY 1000394, a Novel Cyclin-Dependent Kinase Inhibitor, with Potent Antitumor Activity in Mono- and in Combination Treatment upon Oral Application

Phase I study of the safety, tolerability and pharmacokinetics of PHA-848125AC, a dual tropomyosin receptor kinase A and cyclin-dependent kinase inhibitor, in patients with advanced solid malignancies

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