The question used to surprise oncologist Dr. Andrew Hsieh (pictured). It would come at the end of a patient’s appointment after he’d reviewed tests, delivered results, and laid out treatment options. The patient would turn to him and ask, “Well, Doc, what would you do?”
“It’s a heavy question,” said Hsieh, who treats patients with genitourinary cancers. “I’d put it in context of what I’d do if it was my mom, my dad, or myself.”
Too often, there weren’t enough good options for patients, particularly those with metastatic prostate cancer who would respond to a treatment for a while but then it would stop working. Another treatment might work briefly, only to fail again.
A year ago, Hsieh decided to leave the University of California, San Francisco, where he’d done his residency, oncology fellowship, and postdoctoral training to start his own lab at Fred Hutchinson Cancer Research Center and devote himself to research. There, he’s focused on making discoveries that unlock some of the mysteries about how cancer cells work and why some are resistant to treatments, particularly advanced prostate cancer.
“We want to take on interesting and important questions in a daring way. And we have to be daring because people are losing their lives,” he said.
Prostate cancer is the second leading cause of cancer deaths among men in the U.S., second to only lung cancer, according to the American Cancer Society. This year alone, 220,800 new cases of prostate cancer will be diagnosed and about 27,500 men will die of the disease, facts highlighted by the Movember Foundation, which aims to raise awareness about prostate cancer, testicular cancer, and other men’s health issues during the month of November.
Each of those numbers represents a person with a unique story and family, Hsieh knows. For him, it’s also personal. In medical school, he met a fellow classmate who would become his wife. Her father had metastatic prostate cancer and died after the couple got married.
“It galvanized my family and it left a seed in my heart that maybe I could spend my life doing something about this problem – the cellular atrocity, which is what cancer is,” he said.
Hsieh is already making strides in understanding why some prostate cancer is resistant to emerging forms of treatment. A new study co-led by Hsieh and Dr. Davide Ruggero of the University of California, San Francisco, has identified a mechanism that may enable cancer cells to become resistant to some treatments, specifically an emerging class of cancer drugs known as PI3K and mTOR inhibitors. The paper describes how specific populations of prostate cancer cells are uniquely resistant to inhibitors of the PI3K-AKT-mTOR pathway, which is commonly corrupted in human cancer.
This alarming population of drug-resistant cells was found to harbor high levels of a protein known as 4EBP1, an important player in protein production. The study authors found that high 4EBP1 levels decrease protein synthesis within cancer cells and make them immune to PI3K pathway inhibitors.
When the researchers genetically manipulated these cells to reduce 4EBP1, protein production was restored, and the tumor cells once again became sensitive to drug treatment.
Using tumor samples from an ongoing clinical trial led by Dr. Won Kim at the University of California, San Francisco, that is testing an experimental PI3K pathway inhibitor known as buparlisib (BKM120) for men with prostate cancer, the researchers saw that 4EBP1 levels jumped in patient tumors following treatment. Hsieh points to these findings as substantiation of the clinical relevance of their discoveries in the laboratory in mouse models and cancer cell lines.
Identifying which patients will benefit
The finding could eventually be used to predict which prostate cancer patients might benefit most from this class of drugs and those who should not waste precious time with treatments that are likely to fail.
“If we can find the right patient for the right drug, we should,” said Hsieh. “We can use molecular tests to figure out what [medications] for patients to take. That’s ultimately what doctoring is about – helping patients make good informed decisions.”
For some patients who don’t have good options left, it could make the difference between knowing whether to continue treatment and endure more doctor’s visits, tests, and drugs – or whether to stop and spend quality time with loved ones, he said.
Time is something Hsieh, who has two young sons, thinks a lot about. He has a full career ahead of him, but he feels the tug of urgency to do more. While he’s spent the past year getting his lab set up and focusing on research, he’s also planning to start seeing patients again in 2016, both incredibly time-consuming passions.
“You have to do something where not just your brain is in it but your heart. For me, it has to be both,” said Hsieh. It’s a philosophy he saw practiced at home where he was raised by a father who was a pastor and a mother who worked in a lab and examined cells’ characteristics to diagnose early stage cancers.
Her work sparked his interest in the potential of science, particularly when she invited him to peek through a microscope as a boy. “What I thought was just a speck of tissue was actually a whole new world,” he said.
‘I enjoy thinking about problems’
The latest findings also add to a growing field of knowledge showing that how cancer cells make proteins — the cells’ building blocks — matters for disease progression.
Until recently, the cancer research community has primarily viewed changes in DNA and RNA as the instigators of human malignancies, while protein production has been seen as a static and subservient process. “Our findings show that the process of making proteins is just as, if not more so, important than changes in DNA and RNA alone in determining the fate of cancer cells,” Hsieh said.
He believes the findings from these studies aren’t just limited to advanced prostate cancer but could point to how targeting aberrant protein synthesis can potentially be a death knell to all tumors that exhibit this once overlooked process in cancer cell activity.
Hsieh knows that the practical application of his research will come too late for some of his patients, but they are always on his mind as he works.
A big part of being a doctor is being fully present, no matter what the outcome, he said. “I can say ‘I’m walking with you through this thing and you’re going through the next phase of life and I’m here with you.”
And when a patient dies, Hsieh uses his grief as a catalyst that propels his research. “The whole point is this disease is a scourge but let’s do something about it. I’m a curious guy and enjoy thinking about problems. How does it work? How do we fight it? How do we make it so it’s less of a burden or how can we eradicate it?”
Illustration: Fred Hutchinson Cancer Research Center.
Fred Hutchinson Cancer Research Center News Release (11/17/15)
Science Daily (11/17/15)
Abstract (Science Signaling; Vol. 8, Issue 403, ra116 (11/17/15))