Tales from... Dr Kazuaki Takahashi

I grew up watching my father as a doctor treating patients

Dr Kazuaki Takahashi

My family house was located above an obstetrics and gynecology clinic in Japan, and I grew up watching my father as a doctor treating patients. My family life was in a unique environment in that dinner time was determined by the progress of the delivery of babies. Having grown up in such an environment, it was natural for me to wish to be an obstetrician and gynecologist. Obstetrics and gynecology have four major fields: gynecological oncology, maternal-fetal medicine, reproductive endocrinology and infertility, and women's healthcare medicine. I became interested in gynecologic oncology because I was fascinated by ovarian cancer surgery, which is a very dynamic and complicated surgery procedure aiming for complete removal of the cancer that has often spread to many organs in the abdomen. Subsequently, I became a surgical oncologist in Japan. Even with the recent advances in the treatment of ovarian cancer, some patients are still difficult to be cured with surgery and chemotherapy. Therefore, I believe it is important to engage clinical practice with a sound scientific understanding. That is the reason why I am interested in laboratory research.

There are four common types of ovarian cancer that have a wide variety of clinical and biological features. The most common type of ovarian cancer, called high-grade serous ovarian cancer, accounts for about 50-70% of ovarian cancers diagnosed each year. Consequently, over 100,000 women worldwide die annually from this disease, as many patients develop resistance to chemotherapy and PARP inhibitors over time, which is an urgent problem to be overcome. Clear cell carcinoma is another type of ovarian cancer which is more frequent in Asian countries (~25% of ovarian cancers) than in US/Australia/European countries (less than 10%) and are very resistant to conventional chemotherapy. Because of the rarity of these cancers, there are very few clinical trials, and there is an urgent need to develop novel treatments that are effective for these patients.

My recent research in Japan focused on understanding the characteristics of ovarian clear cell carcinoma. I confirmed that this type of ovarian cancer arises from endometriosis by comparing gene mutations in these cancers and endometriosis samples from the same patient. By combining multiple analyses, including testing a variety of drugs on cancer cells to kill the cancer cells, my colleagues and I identified a “druggable” target for cancers with particular gene mutations. We aim to conduct a clinical trial for patients with this drug in the near future.

This experience cemented my desire to do cancer research, and after completing my PhD in Japan, I came to Peter Mac as a visiting scientist in the Bowtell laboratory. The Bowtell laboratory is the world leading lab in ovarian cancer research. Recently, they performed comprehensive characterization of cancer specimens collected from patients with high-grade serous ovarian cancer after chemotherapy. They identified two common mechanisms of cancer acquired resistance to chemotherapy and PARP inhibitors. One involves the cancer cells increasing the levels of a pump on the cell surface that removes chemo-drug. The other involves the cancer cells restoring a DNA damage repair gene which allows the cancer cells to survive under the pressure of chemotherapy. These findings are the result of analysis of tumour samples collected by the CASCADE (Cancer Tissue Collection After Death) program, one of the world's first research autopsy study for ovarian cancer. In addition, the Bowtell Lab identified the genetic characteristics of tumours in long-term survivors with high-grade serous ovarian cancer. Currently, the Bowtell Lab is working with international collaborators to understand why long-term survivors have a good response to chemotherapy and survival at a molecular level.

Interestingly, we have found that cancer cells utilize multiple ways to become resistant within individual patients. We have also found that these events are only present in a subset of the cancer cells. My current work seeks to relate these acquired resistance events to the tumour architecture to understand how the remaining tumour cell population survives treatment. I make use of multiple tumour samples collected through the CASCADE program to determine how these events are spatially distributed across different tumour sites from the same patient and also within individual tumour samples. Understanding the characteristics of resistant cells and how different cells interact will be crucial for overcoming drug resistance and improving prognosis. We are also trying to clarify the genetic characteristics of the tumour in long-term survivors by investigating the mechanism of chemotherapy responsiveness in ovarian cancer cell lines. We believe that detailed molecular and clinical information in long-term survivors will provide important insights to improve the prognosis of patients with ovarian cancer.

My research life at Peter Mac has been fulfilling and exciting. I am supported by a wonderful mentor and other great researchers. Through my research, I would like to contribute to improving the prognosis of patients with treatment-resistant ovarian cancer. Finally, I want to show my greatest appreciation for giving me a chance to my patients and colleagues of the department of obstetrics and gynecology at the Jikei University School of Medicine in Tokyo, Japan.

Figure legend: An ovarian cancer tumour stained to show tumour cells in pink, and the location of the drug pump in yellow. We can see that there are some regions of the tumour with lots of the pump and other regions where there is not much.

Dr Kazuaki Takahashi is a visiting scientist from Japan in the Bowtell Laboratory. He has a background of clinical expertise as a gynecologic surgeon with extensive laboratory research experience, including in the area of molecular genetics of ovarian cancer.

Dr Kazuaki Takahashi can be contacted by:

Email: [email protected]

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