Dr Natalie Briggs

Abstract

Colorectal cancer is a major health problem in New Zealand, with 3000 new diagnoses and 1200 deaths per year. Cancer stem cells (CSC) are a small subpopulation of cells in cancers that can metastasise and initiate new tumours. They contribute strongly to cancer relapse and the failure of standard therapies (such as chemotherapy and radiation) to eradicate most cancers.

However, identifying CSC is complex as they can change phenotype in response to tumour environmental signals and cancer treatment. For example, radiotherapy (RT) can substantially increase signaling and expression of CSC functional markers in rectal cancers, which can increase CSC resistance to RT. Not surprisingly, preclinical studies show that CSC-targeting treatment given with other cancer therapies is more effective than either treatment given alone.

The tetracycline antibiotic doxycycline modulates many CSC metabolic and signalling pathways in various cancers, while enhancing normal stem cell function. Importantly, a small study in breast cancer patients showed that a well-tolerated dose of doxycycline reduced expression of an important CSC functional cell surface marker, CD44, by 44% over 2 weeks, without any other treatment. This offers the potential to use doxycycline with standard cancer therapies to maximize the efficacy of anti-cancer treatments.

The main aim of this trial is to examine whether doxycycline can prevent the RT-induced expression of two CSC markers (CD44 and ALDH1) in rectal cancer patients being treated with “short-course” RT prior to surgery. We will give 20 patients doxycycline tablets during RT and up to the time of surgery (1-2 weeks later), and compare them to 20 patients who had previously been treated with RT then surgery but did not receive doxycycline. Expression of these CSC markers will be scored independently by two pathologists in each patient’s resected tumour, and their diagnostic biopsy taken prior to starting RT. We will compare the change in scores of each CSC marker in patients who had RT with or without doxycycline. We will also evaluate how well rectal cancer patients tolerate doxycycline when given with RT.

If prevention of RT-induced expression of rectal cancer CSC markers by doxycycline is confirmed in this trial, subsequent randomised controlled trials could aim to validate the benefit shown in preclinical studies from adding doxycycline to RT or systemic therapies. This strategy could not only reduce relapse and metastasis rates but also improve survival. It also opens the door to exploring multi-targeted anti-CSC regimens, which appear promising in preclinical studies. This general strategy also offers the potential to greatly improve outcomes of cancer treatment with little toxicity and at trivial cost, making it broadly accessible and helping to reduce inequities in healthcare.

Outcome Statement

If down-regulation of cancer stem cell markers and pathways by doxycycline is confirmed in rectal cancer patients, subsequent randomised controlled trials could be performed to assess for benefits of doxycycline on important cancer outcomes including tumour response, relapse rates and survival. If successful, doxycycline could prove to be a valuable adjuct to our current management of rectal cancer, and potentially other malignancies, with minimal side effects and low financial cost to our health service.