GTN Therapy on Biomarkers of Immune Escape in Men With Biochemical Recurrence of Prostate Cancer After Primary Therapy

Researcher's pre-clinical research has demonstrated that hypoxia-induced tumor cell invasiveness, metastatic ability, resistance to chemotherapeutic agents and evasion of immune cell recognition are inhibited by molecules that activate the NO signalling pathway involving cGMP generation (such as glyceryl trinitrate, GTN), and that pharmacological inhibition of NO signalling results in phenotypes similar to those induced by exposure to hypoxia.

Based on pre-clinical data described above the researchers have recently completed and published a phase 2 trial in patients with recurrent prostate cancer using a low-dose, sustained release trasndermal patch of GTN. The GTN was supplied as Minitran™ (nitroglycerin) transdermal delivery system (3M Company, St. Paul, Minnesota) in an open label, non-blinded fashion. GTN is a nitrodonor that has been used in the management of angina for over 100 years with a well-documented safety and tolerability record and has never been associated with carcinogenesis. Their pre-clinical studies have demonstrated that very low molar concentrations of nitric oxide donors are required to attenuate hypoxia-induced malignant phenotypes.

Our results suggest a significant inhibition of progressive disease given the effect on PSA doubling time with GTN treatment compared to their doubling time prior to initiating the trial. Within 12 months of the trial, 17 of 24 patients had doubling times in the slow category or even stable/declining PSA levels. The mean doubling time of the entire cohort increased to 31.8 months from 13.2 months prior to starting treatment. When compared to a matched control group of patients with PSA recurrence that did not receive any treatment, a similar significant difference in PSA doubling time was observed. There were no adverse effects reported in this trial.

This was the first report of the clinical use of nitric oxide donors in the treatment of prostate cancer. The role of nitric oxide in malignant progression has been a subject of controversy, with studies showing either tumor-promoting or tumor-inhibitory roles. These apparently contradictory effects of NO may be explained by the fact that this molecule can regulate phenotypes through a variety of mechanisms depending on local concentrations and the redox state of the cell. Based on our previous findings, the investigators propose that the observed effect of GTN on the PSA of this patient cohort is related to the 'low concentration' effects of NO.

The investigators have identified several possible beneficial mechanisms of effect of low-dose NO donors for cancer management. We have recently published the positive effect of effect of NO signalling (with GTN as the effector molecule) on cancer immune surveillance. The major histocompatibility complex class I chain-related (MIC) molecules, MICA and MICB, play important roles in tumor surveillance by NK cells, lymphokine-activated killer (LAK) cells, and cytotoxic T cells. While MICA is absent from most normal tissues, they can be induced by cellular stresses, such as exposure to carcinogens and infection, and are expressed in a broad range of carcinomas and some haematopoietic malignancies. In humans, the interaction of cell surface MIC molecules with the C-type lectin-like NKG2D receptor on NK, LAK and effector T cells leads to the activation of innate and adaptive immune responses with the subsequent lysis of the tumor cells. Thus, it has been proposed that MIC-NKG2D interactions are critical to the immune surveillance function of NK, LAK and cytotoxic T cells.

The investigators have shown that hypoxia contributes to tumor cell shedding of MIC through a mechanism involving impaired nitric oxide (NO) signalling. While hypoxia increased MIC shedding in human prostate cancer cells, activation of NO signalling inhibited hypoxia-mediated MIC shedding. Similar to incubation in hypoxia, pharmacological inhibition of endogenous NO signalling increased MIC shedding. These findings suggest that the hypoxic tumor microenvironment contributes to impaired immune surveillance and that activation of NO signalling is of potential use in cancer immunotherapy.

Based on previous studies it is investigator's hypothesis that low-dose transdermal GTN will have positive effects on cancer immune surveillance that may translate to therapeutic benefit. In order to establish proof-of-concept, they propose to initiate the correlative study described in this protocol, to determine the effect of the GTN treatment on biomarkers of immune activity in patients with prostate cancer.