Radical Tumor Denervation Activates Potent Local and Global Cancer Treatment

SIMPLE SUMMARY: The contribution of neuronal innervation to cancer development and persistence is not well understood. In the current study, a novel microsurgical technique for inducing radical and persistent denervation (R&P) on tumor growth was evaluated in a metastatic, solid tumor model in immunocompetent Sprague Dawley rats. Tumors were induced using the mammary adenocarcinoma cell line (HH-16.cl4). Surgical treatment resulted in tumor regression, and led to the long-term survival of the animals, extending to more than >1 year follow-up (long term survival; LTS = 87.5%), indicating the induction of a potent systemic anticancer response. In order to characterize further the anticancer response, multiple tumors were implanted on the same animal and treatment was applied to one of them. Both the treated (primary) and untreated (remote) tumor masses exhibited regression, leading to a 57.1% LTS. The R&P denervation strategy is in line with the results from the current translational research on cancer neurobiology. However, the clinical value of the approach will be verified in a pilot clinical study. ABSTRACT: This preliminary study seeks to determine the effect of R&P denervation on tumor growth and survival in immunocompetent rats bearing an aggressive and metastatic breast solid tumor. A novel microsurgical approach was applied “in situ”, aiming to induce R&P denervation through the division of every single nerve fiber connecting the host with the primary tumor via its complete detachment and re-attachment, by resecting and reconnecting its supplying artery and vein (anastomosis). This preparation, known as microsurgical graft or flap, is radically denervated by definition, but also effectively delays or even impedes the return of innervation for a significant period of time, thus creating a critical and therapeutic time window. Mammary adenocarcinoma cells (HH-16.cl4) were injected into immunocompetent Sprague Dawley adult rats. When the tumors reached a certain volume, the subjects entered the study. The primary tumor, including a substantial amount of peritumoral tissue, was surgically isolated on a dominant artery and vein, which was resected and reconnected using a surgical microscope (orthotopic tumor auto-transplantation). Intending to simulate metastasis, two or three tumors were simultaneously implanted and only one was treated, using the surgical technique described herein. Primary tumor regression was observed in all of the microsurgically treated subjects, associated with a potent systemic anticancer effect and prolonged survival. In stark contrast, the subjects received a close to identical surgical operation; however, with the intact neurovascular connection, they did not achieve the therapeutic result. Animals bearing multiple tumors and receiving the same treatment in only one tumor exhibited regression in both the “primary” and remote- untreated tumors at a clinically significant percentage, with regression occurring in more than half of the treated subjects. A novel therapeutic approach is presented, which induces the permanent regression of primary and, notably, remote tumors, as well as, evidently, the naturally occurring metastatic lesions, at a high rate. This strategy is aligned with the impetus that comes from the current translational research data, focusing on the abrogation of the neuro–tumoral interaction as an alternative treatment strategy. More data regarding the clinical significance of this are expected to come up from a pilot clinical trial that is ongoing.