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

Titre officiel

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

Sommaire:

Le cancer de la prostate est le cancer diagnostiqué le plus souvent chez les hommes au Canada. Plus de 30 % des hommes de plus de 50 ans ont des preuves histologiques de cancer de la prostate à la biopsie. Malgré le stade de migration offert par une détection précoce à l'aide de l'antigène prostatique spécifique (PSA) sérique et une tendance apparente vers une survie améliorée depuis plusieurs années, le cancer de la prostate est toujours une cause importante de morbidité et de mortalité. Des échecs biochimiques après un traitement primaire (chirurgie ou radiation) demeurent un fardeau important des soins de la santé, et des stratégies pour retarder la progression clinique du cancer de la prostate et prolonger l'intervalle entre l'échec du traitement et le traitement systémique serait un bienfait clinique important pour les hommes souffrant d'une récurrence du PSA.

Le PSA est grandement accepté comme le marqueur pronostique le plus utile de la progression du cancer de la prostate, surtout après un traitement primaire de chirurgie radicale ou de radiation. Malgré les taux de contrôle du cancer améliorés par la gestion définitive du cancer de la prostate des premiers stades, une récurrence du PSA est malheureusement une occurrence courante (25 à 50 %) dans la majorité des grandes séries de cas.  

On a prouvé que des facteurs micro-environnementaux jouent un rôle clé dans la sélection de la sous-population de cellules néoplasiques exprimant plus de phénotypes malins et contribuant à la progression de la maladie localisée et métastatique On a très bien décrit des niveaux très faibles d'O2 (< 10 mmHg) dans plusieurs tumeurs solides (y compris le cancer de la prostate) et on a démontré que l'étendue de l'hypoxie représente un marqueur indépendant d'un diagnostic médiocre pour les patients atteints de divers types de cancers. L'hypoxie tumorale contribue à plusieurs phénotypes adaptatifs, y compris une augmentation de l'infiltration et des métastases, ainsi qu'une augmentation de la résistance de l'évasion de la surveillance des cellules immunitaires à la radiothérapie et la chimiothérapie.  Quoique les réponses adaptatives cellulaires à l'hypoxie soient vraisemblablement induites par divers mécanismes, nos études précliniques antérieures indiquent que la signalisation dépendante de l'oxyde nitrique (NO) joue un rôle important dans la progression du phénotype malin.

Description de l'essai

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.

Voir cet essai sur ClinicalTrials.gov

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