Safety and preliminary efficacy data of a novel Casein Kinase 2 (CK2) peptide inhibitor administered intralesionally at four dose levels in patients with cervical malignancies

Abstract

BackgroundCervical cancer is now considered the second leading cause of death among women worldwide, and its incidence has reached alarming levels, especially in developing countries. Similarly, high grade squamous intraepithelial lesion (HSIL), the precursor stage for cervical cancer, represents a growing health problem among younger women as the HSIL management regimes that have been developed are not fully effective. From the etiological point of view, the presence of Human Papillomavirus (HPV) has been demonstrated to play a crucial role for developing cervical malignancies, and viral DNA has been detected in 99.7% of cervical tumors at the later stages. CIGB-300 is a novel cyclic synthetic peptide that induces apoptosis in malignant cells and elicits antitumor activity in cancer animal models. CIGB-300 impairs the Casein Kinase (CK2) phosphorylation, by targeting the substrate's phosphoaceptor domain. Based on the perspectives of CIGB-300 to treat cancer, this "first-in-human" study investigated its safety and tolerability in patients with cervical malignancies.MethodsThirty-one women with colposcopically and histologically diagnosed microinvasive or pre-invasive cervical cancer were enrolled in a dose escalating study. CIGB-300 was administered sequentially at 14, 70, 245 and 490 mg by intralesional injections during 5 consecutive days to groups of 7 – 10 patients. Toxicity was monitored daily until fifteen days after the end of treatment, when patients underwent conization. Digital colposcopy, histology, and HPV status were also evaluated.ResultsNo maximum-tolerated dose or dose-limiting toxicity was achieved. The most frequent local events were pain, bleeding, hematoma and erythema at the injection site. The systemic adverse events were rash, facial edema, itching, hot flashes, and localized cramps. 75% of the patients experienced a significant lesion reduction at colposcopy and 19% exhibited full histological regression. HPV DNA was negative in 48% of the previously positive patients. Long term follow-up did not reveal recurrences or adverse events.ConclusionCIGB 300 was safe and well tolerated. This is the first clinical trial where a drug has been used to target the CK2 phosphoaceptor domain providing an early proof-of-principle of a possible clinical benefit.

Regulation of PTEN by CK2 and Notch1 in primary T-cell acute lymphoblastic leukemia: rationale for combined use of CK2- and -secretase inhibitors

“…This is particularly relevant given the relative inefficacy of GSI treatment in T-ALL patients 14 and recent clinical data in patients with cervical cancer indicating that CK2 antagonists are well tolerated and may have antitumor efficacy. 15 Hence, we treated PTEN-positive T-ALL cell lines with GSI DAPT and/or the CK2-specific inhibitors DRB or TBB. Analyses of cell size (Figure 2A and Online Supplementary Figure S1), total cell counts ( Figure 2B and Online Supplementary Figure S2) and proliferation ( Figure 2C and Online Supplementary Figure S3) revealed that combination of GSI and CK2 inhibitors have a mild but consistent cooperative effect in diminishing leukemia proliferation.…”

Synergistic interactions of the anti-casein kinase 2 CIGB-300 peptide and chemotherapeutic agents in lung and cervical preclinical cancer models

“…The antineoplastic effect of this peptide has been well documented in the preclinical setting in vitro and in vivo (13,17,18). In 2006, the peptide entered a phase I clinical trial on patients with HSILs, where safety and efficacy signs were registered (19). Moreover, in patients with stage 1B2/II cervical cancer, the MTD, biodistribution and modulation of a response biomarker were investigated following local administration of CIGB-300 (20).…”

“…Of note, CIGB-300 exerts a broad antiproliferative effect on cell lines derived from breast, cervical, lung, colon and prostate cancer, while a robust antitumor effect was also observed in vivo in mouse models of cervical and lung cancer (13,17,18). In the clinical setting, CIGB-300 was investigated in a phase I clinical trial on high-grade squamous intraepithelial lesions (HSILs), establishing its safety and tolerability by local injection (19). More recently, another phase I clinical study on patients with stage 1B2/II cervical cancer allowed us to estimate the maximum tolerated dose (MTD) and the pharmacokinetics̸biodistribution profiles for CIGB-300 following local administration (20).…”

From Bench to Clinical Using a Combinatorial Screenings of Phage-Displayed Peptide Libraries

“…CIGB-300 elicits antitumor activity in different animal models when administrated by different routes [9]. As an investigational drug, CIGB-300 was previously tested in a First-in-Human trial where patients with high grade squamous intraepithelial lesion (HSIL) or epidermoid microinvasive cervical cancer received intralesional injections of this peptide-based drug [10]. That was the first clinical trial in which a drug was used to target the CK2 phosphoacceptor domain providing an early proof-of-principle of a possible clinical benefit.…”