Optimizing CIGB-300 intralesional delivery in locally advanced cervical cancer

The CK2-mediated phosphorylation has a significant role in the pathogenesis and development of both solid and haematopoietic tumours (Duncan and Litchfield, 2008; Piazza et al, 2012). Of note, CK2 signalling pathways seem to reinforce biochemical cascades indispensable for tumour growth, proliferation and resistance to conventional and novel cytotoxic agents (Piazza et al, 2012). Therefore, CK2 inhibition could represent a rational therapeutic approach to treat both solid and haematological tumours. In fact, different CK2 inhibitors have already provided successful proof-of-concept for such rationality at the experimental setting (Ahmada et al, 2005; Prudent et al, 2010; Siddiqui-Jain et al, 2010) with perspectives to become a novel cancer-targeted therapeutics in future. Among the CK2 experimental inhibitors, only the CX-4945 small molecule and the CIGB-300 cell-permeable peptide have already reached the clinical stage in phase 1 trials. The CIGB-300 treatment inhibits the CK2-mediated phosphorylation of the B23/nucleophosmin protein-inducing apoptosis in vitro and in vivo and halts tumour growth in animals (Perea et al, 2004, 2008, 2009). Interestingly, it has been observed that a B23/nucleophosmin downregulation on CIGB-300-treated tumour cells (Rodriguez-Ulloa et al, 2010) probably is a consequence of inhibiting the CK2-mediated phosphorylation in such a protein (Tawfic et al, 1995). Importantly, the CIGB-300 treatment modulates a diverse array of proteins involved in apoptosis, cell proliferation, ribosomal biogenesis, anti-cancer drug resistance and angiogenesis in vitro (Rodriguez-Ulloa et al, 2010). Likewise, evidences of synergistic effect between CIGB-300 and some standard chemotherapeutics like cisplatin and paclitaxel, have been also observed both in vitro and in vivo in cervical and lung cancer models (Perera et al, 2014). Such premises along with preclinical data demonstrating the significant antitumour activity of CIGB-300 by intratumour injections in human cervical tumours (Perea et al, 2008), encouraged the subsequent evaluation of this peptide-based drug candidate in patients with cervical malignancies using intralesional injections. Although the systemic routes are preferred for the administration of most anti-cancer drugs, we have hypothesised that local delivery for CIGB-300 could lead to favourable tumour uptake in patients with relative easy-to-access tumours like those ones in the uterine cervix. Under this clinical hypothesis, a First-in-Human trial using CIGB-300 intralesional injections in patients with high-grade squamous intraepithelial lesions demonstrated to be safe and tolerable (Solares et al, 2009). In that study, 90% of the patients experienced a significant colposcopic response, 19% experienced full histological regression and human papillomavirus DNA was negative in 48% of the previously positive patients. Furthermore, CIGB-300 has been also used under compassionate use clauses by this route. Remarkably, a successful antitumour response was observed in a chemoradio refractory patient diagnosed with germinoma who experienced significant tumour shrinking with a sustained improvement of his quality of life after intratumour injection of CIGB-300 (Perea et al, 2011). Finally, a phase 1 trial in patients with cervical cancer FIGO stages IB2/II using 2 ml-intralesional injections of CIGB-300 in a single site on tumours indicated a plateau in terms of tumour uptake between doses of 35 and 70 mg of the peptide (Soriano-Garcia et al, 2013). Therefore, we hypothesised that less volume (1 ml) applied into two equidistant tumour sites would allow a greater CIGB-300 tumour uptake using the highest dose, hence maximising the therapeutic chances for this peptide. This phase 1 trial was designed to investigate the tumour uptake, safety profile and pharmacodynamic activity of CIGB-300 injected in two different sites on tumours at 0.5 ml per injection.