1. Neff Newitt, Valerie

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Identifying novel drivers of metastatic cancer and taking that knowledge back to the clinic is the stuff of professional life for Priscilla Brastianos, MD. But this physician scientist, a native of Vancouver, British Columbia, also works to meet personal goals that fill her heart.

Priscilla Brastianos... - Click to enlarge in new windowPriscilla Brastianos, MD. Priscilla Brastianos, MD

Director of the Central Nervous System Metastasis Program at Massachusetts General Hospital in Boston, with joint appointments at Harvard Medical School and the Broad Institute, Brastianos is a Johns Hopkins-trained oncologist who also did fellowships at Harvard, Mass General, and Dana-Farber. All of that effort seems to have been etched into a predetermined destiny long before Brastianos was born.


Long Ago, Far Away

The story starts in the Greek Isles where her maternal grandparents were born. Her grandmother, determined to follow a medical career, travelled to the mainland city of Thessaloniki, the second largest Greek city, where she became the only woman in her medical class in the mid-1950s.


"While in medical school, she was learning to perform physical examination and breast palpation," told Brastianos. "She palpated her own breasts and diagnosed herself with breast cancer at the age of 23." Having pursued available treatments of the time, her grandmother went on to graduate medical school, marry, and give birth to Maria, Brastianos' mother. "Still dealing with breast cancer, my grandmother went to a rural area of northern Greece to practice because she heard they had no doctor there. At the age of 29, she got up in the dark one early morning and rode on horseback to go deliver a baby. She fell off the horse and it was then discovered that her cancer had spread. Before long, she died of metastatic disease to her spine."


Maria was but a child when her mother died. But she grew up, married, and immigrated with her husband to Canada. She delighted in being mother to two children, Brastianos and her brother. But in time, Maria returned to the rural village where her mother had been the only doctor and found that villagers still remembered the kindly physician. "They remembered the impact she had on their lives," Brastianos recounted proudly. "She was a trailblazer. She not only provided medical care, but she was immersed in the community-taught people how to sew and cook, and tried to help the poor in that region. She wasn't just a physician-she was so much more."


The story set Brastianos, as well as her brother who is now doing a radiation oncology residency in Canada, firmly on medical paths. But then the road took another definitive turn.


"I was in my third year of medical school at Johns Hopkins, bound for neurosurgery, when my mother was diagnosed with breast cancer," she explained. The experience of her mother's terminal cancer journey turned Brastianos' interest to oncology. "We lived through the suffering that goes into chemotherapy, radiation, surgery, and the side effects that limited her quality of life. The sicker she got, the more I was driven to find better treatment options for people with cancer. I held a hope that I would find something for my mom when I started studying metastases, but of course I was too late. The day before my mother passed away she asked me and my brother to promise that we would find better treatments for patients so that one day people wouldn't die of cancer. We both made that promise. We told her we would dedicate our lives to battling cancer and finding treatments for patients." Her mother died of metastatic breast cancer at the age of 57.


Today, Brastianos is knee deep in research, publishing papers and leading clinical trials that all support her promise. While it is serious work, Brastianos admitted, "I love it. I am in Boston, which is such a rich community of science and medicine. I honestly feel when I go to work I am going somewhere to play. It's like going to a candy store every day of my life."


The "candy" is comprised of three primary focuses of her lab. "We study molecular drivers of primary and metastatic brain tumors and their progression, with the goal to identify novel therapeutic targets. Primary brain cancer and metastatic brain cancer from another organ are very different," Brastianos explained. "I like to focus on things that people otherwise do not focus on; I like to chase the unmet clinical needs."


Focus 1: Meningiomas

Prior to a few years ago, little was known about the genomics of a tumor called meningioma, the most common primary brain tumor. Brastianos' group published the first comprehensive genomic study of meningiomas and was first to describe clinically-actionable mutations in meningiomas (Nat Genet 2013;45(3):285-289).


"Now I am running a trial-the first national precision medicine trial in brain tumors-to look at the role of targeted therapies in meningiomas. We have more than 400 hospitals enrolled into the study. It's cool, it's exciting," she said with youthful zeal. "When I think about what is really exciting for me, it is being able to take this knowledge right to clinical use and to patients."


During the trial, patients' tumor samples are sent to Boston for genetic testing. "We will look for one of two key mutations: AKT1 mutations, also found in breast, endometrial, and colorectal cancers, and SMO mutations, also found in basal cell carcinomas," she explained. Inhibitors known for these mutations will be given to patients with these mutations. "The goal is to see if those target therapies are effective in slowing the growth or shrinking meningioma tumors," Brastianos explained.


Focus 2: Craniopharyngiomas

The second area of focus in her lab revolves around craniopharyngiomas, among the rarest of brain tumors numbering only 300 cases per year in the U.S. These rare tumors are associated with a high level of morbidity because of where they are located in the sellar region of the brain-close to the hypothalamus, pituitary gland, and optic nerve. They can be associated with many symptoms. According to the American Brain Tumor Association, "increased pressure within the brain causes many of the symptoms associated with this tumor. Other symptoms result from pressure on the optic tract and pituitary gland. Obesity, delayed development, impaired vision, and swollen optic nerve are common."


"These tumors can be devastating," said Brastianos. "In order to characterize these tumors, we gathered samples from all over the world. There are two subtypes of craniopharyngiomas; we found that 95 percent of one subtype has beta-catenin mutations and 95 percent of the second [papillary] subtype has activating BRAF V600E mutations." Brastianos is now testing the effectiveness of inhibitors that act on the mutations.


"We recently had the opportunity to treat a patient here at Mass General who came in requiring four urgent surgeries over the course of 2.5 months. We had just discovered the BRAF mutations in craniopharyngiomas, so we tested his tumor for BRAF mutation, which we found. After treating him for 34 days with therapy targeting BRAF, his tumor shrank more than 85 percent," Brastianos said. "This is the first time that systemic therapy has ever worked in craniopharyngioma. The tumor shrunk so much that our surgeons were able to remove the rest of it. He got definitive radiation for whatever tumor might be left and he has been free of disease ever since." This case was reported on in the Journal of National Cancer Institute (2015; doi:10.1093/jnci/djv310.0).


"We cured someone," said the oncologist earnestly. "That was the single most satisfying thing I've done in my career to date. It was incredibly gratifying for the whole team. This is why we're in it: to go from the science to the clinic, and take what we learn in the clinic back to the science." Again, the effort resulted in a national trial which started in August 2017 and for which Brastianos serves as principal investigator.


Focus 3: Brain Metastases

The third story in Brastianos' triumvirate of projects involves trying to understand why cancers-breast, lung, melanoma, kidneys, etc.-spread to the brain. "There are two key questions: Do cancers spread to the brain because they have new mutations-new genetic changes-in the brain? Or is it because the drugs are not crossing the blood-brain barrier and are not getting into the brain to do their work? We aim to answer those question and to find new drug targets as well," Brastianos explained.


She noted that, while meningiomas are the most common primary brain tumors, brain metastases are the most common brain tumors of all, with over 300,000 cases in the U.S. each year. Furthermore, patients often die within a few months of diagnosis.


"It is a devastating complication of cancer," said Brastianos. "We see patients who do well combating cancer outside of the brain, only to succumb when the cancer progresses to the brain."


Complicating the issue, said Brastianos, is the fact that most drug companies do not support trials with brain metastases patients. "They exclude those with active metastases because these patients are so sick. I am trying to change that," she declared. "I want to raise awareness and get trials up and running for brain metastases."


Toward that end, she has brought together a group of international collaborators. "I am gathering tumor samples from all over the world-Korea, Spain, Austria, Switzerland, Greece, England, and beyond-to study genetic changes of brain metastases. One of our first steps was to look at genetic changes in brain metastases and compare them to the primary tumors (breast, lung, melanoma, etc.). We have found that more than half of the metastases have new, genetic changes that are clinically-actionable and that are not present in the primary tumors. That has been our most important finding so far. And we did see commonalities, so I have started a clinical trial based on those findings," said Brastianos.


Comprised of tissue that has already been extracted as part of clinical care, the samples will be tested for mutations. Patients will receive inhibitors for mutations when such inhibitors are available. "We need to show that targeting mutations in brain metastases can lead to improved survival. Our hope is tumors will shrink or stop growing. I am leading a pilot study here at Mass General, but we also have a great deal of interest in turning this into a national trial."


Brastianos added: "In less than 2 years, we have gone from DNA to trials in all three of these focus areas. It's a great feeling."


Clearly work is central to Brastianos' life, yet this single woman (who hopes to marry and have a family one day) finds time to practice yoga, run, write poetry, and travel (which gives her an opportunity to use the three languages she speaks). Yet through all of it, she hears her mother calling her back to her primary purpose.


"Every day I remember her voice telling me we need to do better for cancer patients," said Brastianos. "My mother has been my source of inspiration. I truly miss her every day; she left a void. I am determined to keep my promise to her." And the world will benefit from that promise kept.


Valerie Neff Newitt is a contributing writer.


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