In vivo efficacy of melanoma internal radionuclide therapy with a ¹³¹I‐labelled melanin‐targeting heteroarylcarboxamide molecule

Abstract

The development of alternative therapies for melanoma treatment is of great interest as long-term tumour regression is not achieved with new targeted chemotherapies on selected patients. We previously demonstrated that radioiodinated heteroarylcarboxamide ([ 131 I]ICF01012) induced a strong anti-tumoural effect by inhibiting both primary tumour growth and dissemination process in a B16BL6 melanoma model. In our study, we show that a single injection of [ 131 I]ICF01012 (ranging from 14.8 to 22.2 MBq) was effective and associated with low and transient haematological toxicity. Concerning pigmented organs, cutaneous melanocytes and skin were undamaged. In 30% of treated animals, no histological alteration of retina was observed, and in the remaining 70%, damages were restricted to the optic nerve area. Using the Medical Internal Radiation Dose methodology, we determined that the absorbed dose in major organs is very low (<4 Gy) and that a delivery of 30 Gy to the tumour is sufficient for an effective anti-tumoural response. Molecular analyses of treated tumours showed a strong radiobiological effect with a decrease in proliferation, survival and pro-angiogenic-related markers and an increase in tumour suppressor gene expression, melanogenesis and anti-angiogenic markers. All these features are in accordance with a tumour cell death mechanism that mainly occurs by mitotic catastrophe and provide a better understanding of in vivo anti-tumoural effects of Metastatic melanoma has a poor prognosis with an estimated death rate ranging from 1.8 to 3.5 per 100,000 cases worldwide. 1,2 As with other cancers, chemotherapy (dacarbazine) remained the conventional treatment with poor benefit for over half a century. Two strategies have improved melanoma treatment, one using the tumour immune response by blocking cytotoxic T-lymphocyte activation (antibody anti-CTL4) 3 and the other targeting BRAF. 4 A recent multicentre phase 1 clinical trial testing a mutated BRAF (V600E) inhibitor showed complete or partial tumour regression in the majority of patients. 5 However, BRAF mutations are detected in only 60% of melanoma cases, and the therapy involves selection of patients with tumours that carry the V600E BRAF mutation. 5,6 Furthermore, most treated patients acquire resistance to this inhibitor after initial clinical response. 7 Metastatic melanoma is always described as a refractory disease, and new observations suggest that combined therapies will have a greater impact on melanoma residual activity. As the mechanisms of resistance to treatment rely on tumour adaptation by somatic mutations, 8 other non-protein targets such as melanin could be considered for future therapies.Melanin pigment is detected in more than 90% of primary melanoma cases, and thus, a strategy targeting this pigment

Melanoma-targeted delivery system (part 1): Design, synthesis and evaluation of releasable disulfide drug by glutathione

“…The capacity of these amorphous, irregular polymers to bind to many drugs, especially those with coplanar fused aromatic rings and/or polyamine side chains, make it a promising target for a pigmented melanoma-targeting strategy [11,17]. Based on these findings, in the last two decades our research group has developed arylcarboxamide families that have potential applications for PET imaging [18e20] and/or targeting radionuclide therapy [21,22] of melanoma due to their rapid, specific and long-lasting tumour uptake. We are now exploring the use of such Melanin-Targeting Probes (MTPs) [23] to carry an anticancer drug into the melanoma tumour site [24,25].…”

Radiation dosimetry of [131I]ICF01012 in rabbits: Application to targeted radionuclide therapy for human melanoma treatment

“…We already investigated effectiveness of [ 131 I]ICF01012 for therapeutic targeting of melanin‐positive melanoma in mice through in vivo experiments coupled with dose calculations to organs of interest using the GATE Monte Carlo platform . It was shown that, in C57BL6 mouse model highly pigmented eyes, the uptake of [ 131 I]ICF01012 was significant, with an absorbed dose to eyes of 117.2 Gy while 96 Gy were delivered to the tumor for an injected activity of 37 MBq.…”

Theranostic Approach for Metastatic Pigmented Melanoma Using ICF15002, a Multimodal Radiotracer for Both PET Imaging and Targeted Radionuclide Therapy

“…This dose induced tumor growth inhibition with DTs of 2.92 ± 0.45 days in treated group as compared with 1.80 ± 0.25 days in controls. TRT was associated with an early increase in both G2/M and sub-G1 blockage, with the induction of P53S15 phosphorylation leading to P21 expression and to cell death, as observed for similar TRT approaches [19], [29]. P21 expression is known to be dependent of P53 transcriptional activation, and both P21 and P53 control the G1/S and G2/M cell cycle checkpoints.…”

“…At later stages of TRT, VEGF downregulation and extracellular melanin increase were also evidenced. Such extracellular melanin release may be considered as an additional target for a second TRT round [19], [30], [31].…”

“…In preclinical studies, this radiotracer demonstrated promising results in primary and metastatic melanoma models, with superior contrast and specificity in pigmented-melanoma models [16]. For melanin-targeted radionuclide therapy (TRT), many arylcarboxamide derivatives such as [ 131 I]MIP-1145 and [ 131 I]ICF01012 exhibited a strong efficacy in murine and human melanoma xenografts [17], [18], [19]. A first clinical study using the analogue [ 131 I]BA52 demonstrated promising survival benefits and favorable dosimetry in patients with metastases, strengthening the high potential of this class of compounds for TRT of melanotic tumors [20].…”