[Note: This project was funded before we started writing up individual stories for projects.]
The overall hypothesis of our program is that the dynamic nature of the tumour microenvironment is an important contributor to the development, behaviour and prognosis of many solid cancers. Tumour cells sense and respond to their microenvironment through distinct biological pathways that contribute to aggressive tumour behaviour and treatment response. The current program consists of 4 funded and 2 leveraged projects with clinical, pre-clinical and basic science objectives. We are characterizing the nature and importance of the tumour microenvironment in cervix, prostate, and pancreatic tumours in clinical trials of novel targeted agents through measurements of hypoxia, IFP, perfusion, metabolism and energy status using a range of 2D, 3D and 4D imaging methodologies. These efforts are supported by development of advanced 4D imaging and analysis techniques with a focus on molecule transport in tumours. The clinical studies are directly integrated with fundamental studies into the nature of oxygen sensing in tumours and the influence of hypoxia on signalling pathways that influence important tumour phenotypes including cellular metabolism, DNA repair, stemness, and metastasis. Teams of principal investigators, fellows, students, and technicians in each of these projects collaborate extensively and integrate seamlessly with the common goal of improving cancer treatment through targeting hypoxia and other features of the unique tumour microenvironment.
Recent discoveries and accomplishments
- Developed an approach to handle complex biomarker information within solid tumours
- Over 350 patients have been accrued to clinical trials in prostate and cervix cancer in which information regarding hypoxia has helped to define new cancer therapies
- Showed that hypoxia is associated with biochemical relapse after radiation for prostate cancer
- IFP is a biomarker of chemo-radiation response in cervix cancer
- Hedgehog signalling is associated with hypoxia in cervix cancer biopsies
- Developed novel approaches to map altered trans-capillary and interstitial fluid dynamics in solid tumours that which underlie high IFP, the EPR effect and impaired delivery and transport of nutrients and therapeutic agents using scalable liposomal imaging contrast agents
- Developed a novel method to assess tumour perfusion with a reduction of CT dose to patients by 5 to 10 fold. This reduction will increase safety and enable longitudinal studies during treatment. (selected as an Editor’s pick in the August, 2011 issue of Medical Physics).
- Showed that hypoxic cells can acquire deficiency in DNA repair due to altered protein translation of DNA repair genes as the basis of genetic instability
- Repair-deficient hypoxic cells may now be considered as targets of novel molecular targeted agents, such as PARPi inhibitors (highlighted by Nature Reviews Cancer and Nature Reviews Drug Development in 2011)
- Identified hypoxic regulation of mTOR signalling and metabolic activity in cancer and demonstrated the potential of targeting this pathway to improve radiation response
- Showed that activation of the unfolded protein response mediates hypoxia tolerance through regulation of autophagy
- Demonstrated the importance of mRNA translational control in mediating changes in gene expression during hypoxia 42
- Showed that cyclic hypoxic enhances lymphatic metastasis in orthotopic cervix cancer models including patient-derived xenografts (simulates clinical findings).
- Demonstrated that blocking the action of the hypoxia induced gene VEGF-C and its receptor VEGFR3 prevents hypoxia induced increase in metastasis
- Demonstrated a highly significant association between hypoxia and aggressive biology in patient-derived pancreas cancer xenografts. This suggests that hypoxia is major adverse prognostic feature of pancreas cancer, and supports testing novel agents to target hypoxia
List of Key Publications
- Kim SM, Haider MA, Milosevic M, Jaffray DA, and Yeung IWT: A method for patient dose reduction in dynamic contrast enhanced CT study. Med. Phys: 38, 5094-5103 (2011).
- Chan N, Pires I, Benkocova Z , Coackley C , Bhogal N , Lakshman M , Gottipati P , Oliver J, Helleday T , Hammond E, Bristow RGF. Contextual Synthetic Lethality of Cancer Cell Kill Based on the Tumor Microenvironment. Cancer Research: 70(20):8045-54 (2010).
- Kumareswaran R, Ludkovski O, Meng A, Sykes J, Pintilie M, and Bristow R. Chronic hypoxia compromises DNA doublestrand break repair to drive genetic instability. J Cell Science: In Press-first issue - Jan (2012).
- Rouschop KM, Dubois L, Schaaf MB, van den Beucken T, Lieuwes N, Keulers TG, Savelkouls KG, Bussink J, van der Kogel, AJ, Koritzinsky M, Wouters BG, Deregulation of cap-dependent mRNA translation increases tumour radiosensitivity through reduction of the hypoxic fraction. Radiotherapy and Oncology: June (2011).
- Pintilie M, Iakovlev V, Fyles A, Hedley D, Milosevic M, Hill RP. Heterogeneity and power in clinical biomarker studies. J Clin. Oncol: 27:1517-1521 (2009).
- Chopra S, Toi A, Taback N, Evans A, Haider MA, Milosevic M, Bristow RG, Chung P, Bayley A, Morton G, Vesprini A, Warde P, Catton C, Menard C. Pathological Predictors for site of Local Recurrence after Radiotherapy for Prostate Cancer, Int J Radiat Onc Biol Phys: In Press (2011).
- Herrera FG, Vidal L, Oza A, Milosevic M, Fyles A. Molecular targeted agents combined with chemo-radiation in the treatment of locally advanced cervix cancer. Rev Recent Clin Trials: 3:111-20 (2008).
- Rouschop KM., van den Beucken T, Dubois L, Niessen H, Bussink J, Savelkouls K, Keulers T, Mujcic H, Landuyt W, Voncken JW, Lambin P, van der Kogel AJ, Koritzinsky M, Wouters BG. The unfolded protein response protects human tumour cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5.J Clin Invest: 120(1): p.127-41 (2010).
- Chaudary N, Milosevic M, Hill RP. Suppression of vascular endothelial growth factor receptor 3 (VEGFR3) and vascular endothelial growth factor C (VEGFC) inhibits hypoxia-induced lymph node metastases in cervix cancer. Gynecol Oncol: Nov;123(2):393-400 (2011). Epub 2011 Aug 12.
- Chaudary N, Pintilie M, Hedley D, Fyles AW, Milosevic M, Clarke B, Hill RP, Mackay H. Hedgehog pathway signaling in cervical carcinoma and outcome after chemoradiation. Cancer: Oct 25 (2011). doi: 10.1002/cncr.26635. [Epub ahead of print].
- Chang Q, Do T, Jurisica I and Hedley DW: Hypoxia predicts aggressive growth and spontaneous metastasis formation from othotopically-grown primary xenografts of human pancreatic cancer. Cancer Research: 71: 3110-3120 (2011).