Chemo-Radiotherapy of Oligometastases of Colorectal Cancer With Pegylated Liposomal Mitomycin-C Prodrug (Promitil): Mechanistic Basis and Preliminary Clinical Experience

Esther Tahover, Rachel Bar-Shalom, Eli Sapir, Raphael Pfeffer, Igor Nemirovsky, Yehonatan Turner, Maya Gips, Patricia Ohana, Benjamin W Corn, Andrew Z Wang, Alberto A Gabizon, Esther Tahover, Rachel Bar-Shalom, Eli Sapir, Raphael Pfeffer, Igor Nemirovsky, Yehonatan Turner, Maya Gips, Patricia Ohana, Benjamin W Corn, Andrew Z Wang, Alberto A Gabizon

Abstract

Hypo-fractionated radiotherapy and stereotactic body radiotherapy are viable options for treatment of oligometastases. A prodrug of mitomycin-C is under clinical testing as a pegylated liposomal formulation (Promitil) with an improved safety profile over mitomycin-C. Promitil was offered to two patients with oligometastases from colorectal cancer as radiosensitizer. Each derived durable clinical benefit from Promitil administered immediately prior to and following irradiation. Transient toxicity to normal tissues of moderate to severe degree was observed. Promitil appears to have potential clinical value in this setting. HIGHLIGHTS - Delivery of radio-sensitizing drugs with pegylated (long-circulating) liposomes is a pharmacologically rational approach which remains largely clinically untested.- A mitomycin-c prodrug delivered by pegylated liposomes (Promitil) is activated by thiol groups, which are produced in excess by radiation-damaged cells, thus potentiating the radio-sensitizing effect of Promitil.- Two durable clinical responses in patient with colorectal oligometastases to Promitil and radiotherapy suggest that this approach may be of value in cancer chemo-radiotherapy.

Keywords: colorectal cancer; liposomes; mitomycin-C; oligometastases; prodrug; radiosensitizer; radiotherapy.

Figures

Figure 1
Figure 1
(A,B) represent PET-CT images of two different pelvic metastases in the radiation field. Upper panel of (A,B): PET/CT on 30Sep2015, before Promitil with radiotherapy. Lower panel of (A,B): PET/CT on 28Dec2016, 15 months after Promitil with radiotherapy. Axial CT (left panel), FDG PET (middle panel) and fused FDG PET/CT (right panel) images of two metastatic lesions. The intense pathological uptake in a left nodule anteriorly to the rectal anastomosis (A, arrows) and in a right para-rectal nodule (B, arrows) has completely resolved with therapy on both PET and CT, along a prolonged follow-up (A,B, lower panel). Note post radiation rectal wall thickening on post-therapy CT images.
Figure 2
Figure 2
Tumor marker response to Promitil with radiotherapy. Same patient as in Figure 1. Note the sustained decrease of CEA and Ca19-9 levels after chemo-radiotherapy.
Figure 3
Figure 3
Axial CT (left panel), FDG PET (middle panel) and fused FDG PET/CT (right panel) images before Promitil with radiotherapy (A, 07Apr2016), 3 months after Promitil with radiotherapy (B, 04July2016), and on a recent re-evaluation 22 months later (C, 19Feb2018). Initial pre-therapy intense pathological uptake in two adjacent porto-caval lymph nodes (arrows) resolved after therapy, with significant interval reduction in lymph nodes dimensions.
Figure 4
Figure 4
Graphical representation of the proposed mechanism of radio-sensitization by Promitil. The process includes the following steps in sequence. (A) Promitil reaches tumor site via EPR effect, limited prodrug activation and MMC release takes place in tumor initiating the radio-sensitizing effect. (B) Radiation-damaged cells secrete SH compounds that activate the prodrug MLP amplifying the generation of MMC and subsequent radiosensitizing effect by alkylation and formation of DNA adducts. (C) Schematic drawing of the prodrug MLP with the disulfide bridge sensitive to free thiols and leading to the release of MMC. Adapted with permission from Tian et al. (11).

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