PERSONALISED CANCER THERAPEUTICS

Pancreatic cancer is one of the deadliest forms of cancer, which still kills 94% of the people it afflicts. The average survival of metastatic pancreatic cancer patients, even with treatment is only 6 months and novel treatment approaches are desperately needed.

Our vision is to build on our recent discoveries in the field of cancer genomics (published in Nature 2012, 2013, 2015, 2016 and 2017) to develop novel personalised approaches for the treatment of both primary operable and metastatic pancreatic cancer. Our team is multidisciplinary, comprising individuals from diverse disciplines ranging from basic biology, laboratory discovery and preclinical testing, biomarker development and implementation.

Cutting edge tools to study pancreatic cancer:

We have established a unique Australian resource, comprising of well annotated patient-derived xenografts of pancreatic cancer and a large well annotated panel of patient-derived cell lines from the patients that have been sequenced as part of the International Cancer Genome Consortium. Collectively, these models represent an invaluable resource of renewable material for the discovery of biomarkers and testing novel therapeutic combinations, and are readily available to the wider research community; please see: http://www.pancreaticcancer.net.au/bioresource-pdcls/

Our research program centres on two key areas: :

(i) Validating new drug targets and developing optimal combination therapies for the treatment of pancreatic cancer. These activities will rely on my expertise in the development of pancreatic patient-derived xenograft (PDX), cell line (PDCL) transplant models and new organoid-based co-culture models to study the intricate interactions between specific cancer-specific signalling components and key cues from the microenvironment and how these may be modulated with novel drug combinations (see our publications in Gut, Sci Transl Med).

(ii) To better understand how anti-cancer drug resistance develops. To this end, we are applying a combination of whole genome sequencing, transcriptomic and other molecular analyses to document the emergence of chemoresistance in pancreatic cancer. The unique design of our ongoing preclinical personalised trials enables effective assessment of intrinsic and acquired therapeutic resistance (for example our studies in Nature (2015), Clin Cancer Res (2017) and Cancer Res (2018). Our ultimate goal is to refine tailored treatment strategies for PC, overcome or circumvent treatment resistance and build optimal, effective treatment combinations for patients with this disease.

 

 

 

Selected Publications

Chou A, Froio D, Nagrial AM, Parkin A, Murphy KJ, Chin VT, Wohl D, Steinmann A, Stark R, Drury A, Walters SN, Vennin C, Burgess A, Pinese M, Chantrill LA, Cowley MJ, Molloy TJ; Australian Pancreatic Cancer Genome Initiative (APGI), Waddell N, Johns A, Grimmond SM, Chang DK, Biankin AV, Sansom OJ, Morton JP, Grey ST, Cox TR, Turchini J, Samra J, Clarke SJ, Timpson P, Gill AJ, Pajic M. Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer. Gut 2017 Oct 28. [Epub ahead of print]

Vennin C, Chin VT, Warren S, Lucas MC, Herrmann D, Melenec P, Walters SN, Magenau A, Allam AH, McCloy RA, Conway JRW, Pinese M, Boulghourjian A, Zaratzian A, Heu C, Nagrial AM, Chou A, Steinmann A, Drury A, Froio D, Giry-Laterriere M, Harris NLE, Mcghee EJ, Whan R, Grey S, Johns AL, Samra JS, Chantrill L, Gill AJ, Biankin AV, APGI, Wang Y, Evans TRJ, Anderson KI, Samuel MS, Burgess A, Sansom OJ, Morton JP, Pajic M*, Timpson P*. * Co-last and co-corresponding authors. Transient tissue ‘priming’ via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy and the onset of the metastatic niche. Science Translational Medicine 2017 9(384). pii: eaai8504.

Pajic M, Froio D, Daly S, Doculara L, Millar EK, Graham P, Drury A, Steinmann A, de Bock CE, Boulghourjian A, Zaratzian A, Carroll SL, Toohey JM, O’Toole SA, Harris AL, Buffa FM, Gee HE, Hollway G, Molloy TJ. miR-139-5p modulates radiotherapy resistance in breast cancer via repression of multiple DNA repair and reactive oxygen species defence gene networks. Cancer Research 2018 78(2):501

Pajic M, Blatter S, Guyader C, Gonggrijp M, Kersbergen A, Sol1 W, Drost R, Jonkers J, Borst P, Rottenberg S. Selected alkylating agents can overcome drug tolerance of G0-1 like tumor cells and eradicate BRCA1-deficient mammary tumors in mice. Clinical Cancer Research 2017 23(22):7020

Vennin C, Murphy K, Cox T, Morton J, Pajic M* and Timpson P*. *  Co-last and co-corresponding authors. Reshaping the tumor stroma: emerging therapies in pancreatic cancer. Gastroenterology 2018 154(4):820-838

Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, Miller DK, Christ AN, Bruxner TJ, Quinn MC, Nourse C, Murtaugh LC, Harliwong I, Idrisoglu S, Manning S, Nourbakhsh E, Wani S, Fink L, Holmes O, Chin V, Anderson MJ, Kazakoff S, Leonard C, Newell F, Waddell N, Wood S, Xu Q, Wilson PJ, Cloonan N, Kassahn KS, Taylor D, Quek K, Robertson A, Pantano L, Mincarelli L, Sanchez LN, Evers L, Wu J, Pinese M, Cowley MJ, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chantrill LA, Mawson A, Humphris J, Chou A, Pajic M et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 2016 531(7592):47-52

Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, Johns AL, Miller D et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 2015 518(7540):495. * Significant national coverage, including interviews with Dr Pajic for SBS and Channel 7 national news.

Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio S, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Børresen-Dale A-L, Boyault S, Burkhardt B, Butler AP, Caldas C, Davies HR, Desmedt C, Eils R, Eyfjörð JE, Foekens JA, Greaves M, Hosoda F, Hutter B, Ilicic T, Imbeaud S, Imielinsk M, Jäger N, Pajic M. et al. Signatures of mutational processes in human cancer. Nature 2013; 500(7463):415-21.

Chang DK, Johns AL, Scarlett CJ, Pajic M. et al. Molecular Pathological Phenotypes and Outcome in Adenocarcinoma of the Ampulla of Vater. Journal of Clinical Oncology 2013; 31(10):1348-56.

Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, Miller DK, Wilson PJ, Patch AM, Wu J, Chang DK, Cowley MJ, Gardiner BB, Song S, Harliwong I, Idrisoglu S, Nourse C, Nourbakhsh E, Manning S, Wani S, Gongora M, Pajic M. et al. Genomic Analysis Reveals Roles for Chromatin Modification and Axon Guidance in Pancreatic Cancer. Nature 2012 491(7424):399-405.

Pajic M, Scarlett CJ, Chang DK et al. Preclinical strategies to define predictive biomarkers for therapeutically relevant cancer subtypes. Human Genetics 2011; 130(1):93

Pajic M, Iyer JK, Kersbergen A, et al. A moderate increase in Mdr1a/1b expression causes in vivo resistance to doxorubicin in a mouse model for hereditary breast cancer  Cancer Research  (2009) 69 16:6396


More Garvan Publications

Staff in the Group

Dr Angela Chou

Research Officer

Ali Drury

Animal Technician

Danielle Froio

Research Assistant

Shihab Hasan

Research Officer

Isuru Hewage

Visiting Scientist

Jennifer Man

PhD Scholar

Erin Mosmann

Animal Technician

Ashleigh Parkin

PhD Student

Rhys Stark

Research Assistant

Angela Steinmann

Research Assistant

Nicolas Vogel

Research Assistant

Julia Yin

Research Assistant

Diseases We Research
Pancreatic cancer

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