Official Title
A Double-Blind, Randomised, Placebo-Controlled Study of the Effect of Transdermal Nitroglycerin (Glyceryl Trinitrate; GTN) Therapy on Biomarkers of Immune Escape in Men With Biochemical Recurrence of Prostate Cancer After Primary Therapy
Summary:
Prostate cancer is the most commonly diagnosed cancer in men in Canada. Over 30% of men over
the age of fifty have histological evidence of prostate cancer on biopsy. Despite the stage
migration afforded by early detection with serum prostate specific antigen (PSA) testing and
an apparent trend toward improved survival over the past several years, prostate cancer
remains a significant cause of morbidity and mortality. Biochemical failure after primary
therapy (surgery or radiation) remains a significant health care burden and strategies to
delay clinical prostate cancer progression and prolong the interval from treatment failure to
systemic therapy would be of significant clinical benefit for those men suffering from a
finding of PSA recurrence.
PSA is widely accepted as the most useful prognostic marker of prostate cancer progression,
particularly after primary therapy with radical surgery or radiation. 5 Despite improved
cancer control rates with definitive management of early stage prostate cancer, a PSA
recurrence is unfortunately a common occurrence (25-50%) in most large case series.
Microenvironmental factors have been demonstrated to play a pivotal role in the selection of
neoplastic cell subpopulations expressing more malignant phenotypes and contributing to the
progression of localized and metastatic disease. Very low levels of O2 (< 10 mmHg) has been
well described in many solid tumours (including prostate cancer) and the extent of hypoxia
has been demonstrated to represent an independent marker of a poor prognosis for patients
with various types of cancers. Tumour hypoxia contributes to numerous adaptive phenotypes
including increased invasion and metastasis, as well as evasion of immune cell surveillance
increased resistance to radiation therapy and chemotherapy. Although cellular adaptive responses
to hypoxia are likely mediated by various mechanisms, our previous preclinical studies
suggest that decreased nitric oxide (NO)-dependent signalling plays a significant role in
this progression of a malignant phenotype.
Trial Description
Primary Outcome:
- Change in the following biomarkers: inflammatory/immune markers uPAR, PAI-1, ULBP2, B7-H1, MIF, TGF-β; and PSA compared to placebo.
Secondary Outcome:
- Safety and tolerability of SR low-dose GTN patches in the proposed patient population.
Researcher's pre-clinical research has demonstrated that hypoxia-induced tumour 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 tumour-promoting or tumour-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 tumour 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 tumour 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 tumour 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
tumour 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.
View this trial on ClinicalTrials.gov
