“Cancer is hideous and deplorable and must be conquered, and it will be, as any evil eventually is defeated" - Jon M. Huntsman
For four years in America as I sat down to my laboratory desk every morning, this quote by Jon Huntsman, a four-time cancer survivor who lost his parents to the disease and whose name is synonymous with cancer research through the Huntsman Cancer Institute, greeted me. Reading it always reminded me that regardless of what experimental roadblocks I faced the day before that today was a new day to suit up and join the crusade against this nefarious disease.
In 2018 alone, 18.1 million new cancer cases were diagnosed globally with approximately 9.6 million cancer deaths documented. Although new technologies and comprehensive genomic analysis have paved the way for a paradigm shift in the diagnosis, classification, and treatment of many cancer subtypes, the invariable emergence of drug resistance remains the foremost threat in the present therapeutic era. One key aspect towards realizing the potential of new and traditional therapies is a better understanding of the intrinsic and acquired resistance mechanisms that limit their efficacy.
I have always been fascinated by the multitude of mechanisms that tumour cells employ to resist targeted agents. As such, since 2010, the primary focus of my research has been to unravel mechanisms of solid tumour sensitivity and resistance to novel therapeutic agents, primarily in Ewing sarcoma, a rare paediatric bone malignancy. After a NHMRC fellowship position at Nationwide Children’s Hospital (Ohio, USA), I recently joined the Bowtell laboratory (Peter MacCallum Cancer Centre) in 2018, which focuses on High Grade Serous Ovarian Cancer (HGSOC).
HGSOC remains a salient public health concern and significant source of global mortality, accounting for 70–80% of all ovarian cancer deaths worldwide. Recently, the Bowtell laboratory identified the most common mechanism of acquired drug resistance in HGSOC to date, a transcriptional fusion involving ABCB1, the gene encoding the drug transporter P-glycoprotein (P-gp). P-gp is drug efflux pump that flushes anti-cancer drugs out of the cell, thereby leading to drug resistance by minimising the effectiveness of cancer therapy. Interestingly, our research demonstrated that ABCB1 fusion events were only detected in patients who had been exposed to chemotherapies that are known to interact with P-gp. In addition, our whole genome sequencing analysis of patient samples revealed that not all tumour cells in fusion-positive patients carry the fusion.
We believe that when you expose a tumour comprised of a mixture of fusion-positive and fusion-negative cells to drugs that P-gp can actively pump out, the fusion-negative cells will undergo cell death whilst the fusion-positive cells will remain unaffected. In other words, specific types of therapy are selecting for fusion-positive cancer cells - it is a classic survival of the fittest!
Tracking immune cells in ovarian tumours
My current role is to examine how the presence of this unique fusion alters the basic biology of ovarian cancer cells, and how different ratios of fusion-positive/negative cells effects cellular growth and drug sensitivity. We believe that resistance within tumour sites is spatially ordered rather than random. That is, it is plausible that ABCB1 fusions are required where chemotherapy concentrations are highest (ie. close to blood vessels) but are less important for tumour cells located in poorly perfused stroma. Identifying such patterning and how the interaction of fusion-negative/positive cells influences drug sensitivity and response to tumour microenvironment, could explain why complete tumour eradication has not been achieved to date.
With approximately 140,000 women dying from HGSOC globally each year, any new insights into the pathogenesis, molecular underpinnings and diversity of drug resistance mechanisms in ovarian cancer has the potential to provide better treatment options and to improve outcomes for women living with this debilitating malignancy.
When I started my Science degree, no one foreshadowed the roller coaster journey I would encounter. The high, lows, twists and curveballs that ensue after every successful grant, failed experiment, rejected manuscript or perplexing result. However, it is a privilege to work at the Peter MacCallum Cancer Centre with dedicated scientists, clinicians and leading core facilitates that all exemplify innovation and excellence.
As I leave through the Peter Mac research doors every day, I remember what a dear friend of mine, a two times cancer survivor, recently said to me on his birthday. “I hope to have as good a day as any, above the grass is always a plus”. I ask you, as you leave work today and reflect on the challenges and highlights of the week, look at the patients who are fortunate enough to be treated at our world class institute and remember that they are currently living through the hardest battle of their lives. With every small finding we discover, our duty as scientists is to support these patients, with the hope that one day we can strike the word “cancer” from the dictionary.
Dr Kathleen Pishas is a CJ Martin NHMRC Postdoctoral Fellow in the Bowtell Laboratory. Her expertise includes Ewing sarcoma, and mechanisms of innate and acquired solid tumour drug resistance.
She can be contacted by email at [email protected].