When the National Brain Tumor Society’s legacy organizations – The Brain Tumor Society (BTS) and the National Brain Tumor Foundation (NBTF) – were founded in the 1980’s, brain tumor research was still, in essence, in its infancy. Very little was understood about the underlying biology of these tumors or, subsequently, how to treat them.
Thus, BTS and NBTF were founded to help the field move ‘out of the wilderness,’ so to speak. The early efforts from each of these organization helped funnel money into research and draw interest and attention to this area of major unmet medical need. It is not a stretch to say that NBTS – through its legacy organizations – played a significant role in building the neuro-oncology field to what it is today. Early support for, and championing of, brain tumor research from BTS and NBTF helped establish what are, today, some of the most prolific and pioneering brain tumor research labs in the world as well as put brain tumors on the national map.
Below are excerpts from a recent interview with Dr. Howard A. Fine, an internationally renowned neuro-oncologist both in terms of laboratory research, clinical trials, and patient care. Dr. Fine is the Founding Director of the Brain Tumor Center and Chief of the Division of Neuro-Oncology at Weill Cornell Medicine and New York-Presbyterian. Previously, he had built large multidisciplinary brain tumor programs at top cancer centers like NYU Langone Medical and the Dana Farber Cancer Institute/Harvard Medical School. He was also the founding Chief of the Neuro-Oncology Branch at the National Institutes of Health (NIH) and National Cancer Institute (NCI).
Dr. Fine received his first-ever brain tumor research grant from BTS and credits the organization with helping jumpstart his career.
Recently, Dr. Fine was awarded a prestigious five-year, $6 million NIH Director’s Pioneer Award for his, “innovative approach to modeling deadly brain cancers in the laboratory — an approach that could be crucial for the development of effective therapies.”
We spoke with Dr. Fine about this award, his research over the years, how he’s seen the field grow since his first grant from BTS, and where he sees the field headed:
On receiving his first grant from BTS:
“It’s an important step to allow you both the time and legitimacy [to move forward with your career].”
On how his career has progressed since receiving the BTS grant and establishing his lab:
“We were one of the first groups to describe glioma stem cells. So for the last 15 years we’ve been really interested in better modeling primary gliomas, both for the sake of identifying novel therapeutic targets, as well as for better understanding of glioma biology and for screening purposes. That’s the laboratory-based stuff. Then as a physician-scientist, the Holy Grail – and I’m trying to live by that – is to try and take stuff that we do in the laboratory and move it to the clinic. And many of the clinical trials I’ve conducted are either direct or indirect spin-offs from advances we made in the laboratory.”
On how he’s seen attitudes toward brain tumor research at the national level change over his career:
“When I started out in the field 30 years ago, no one was giving any attention to brain tumors – whether it be at the basic science level; the NIH-funding level; the FDA didn’t have any special knowledge of brain tumors; and the pharmaceutical and biotechnology industry had no interest in brain tumors – they were very nihilistic about the problem. I think that has all changed very dramatically…As it relates to the Pioneer Award for example, they only give out 8-12 every year – and it’s important to note that’s not through the NCI or NINDS (National Institute of Neurological Disorders and Stroke). It’s the entire NIH; so all diseases [not just cancer]. And if you look at who won these awards this year, of the 12, only two – including my own – were cancer related. The other ones were [other] diseases.”
On how he sees his work, as well as the overall brain tumor research field, moving forward:
“I think we’ve made tremendous progress. I think we’ve caught up to systemic tumors in terms of our understanding of basic biology – and in many ways have gone past them as far as genomics. We know more about glioblastoma genomics than many tumor types, if not most tumor types, thanks to the TCGA (The Cancer Genome Atlas).
So I think the future will continue to be bright, in terms of knowledge gained. I think the question now is, where is the successful translation? Meaning not just getting stuff from the lab to the clinic, as we and others have done, but getting successful stuff to the clinic and impacting patients.
Where the field is right now, is where I think it should be…but there’s also a part of me that says, this is a very, very different tumor type biologically, clinically, and otherwise than other tumor types, and maybe taking the approach we’re taking for others cancers may not necessarily be the only good way to approach this tumor. So I think there’s room for a segment of researchers to possibly take a different look at how we approach this disease biologically, and then, hopefully, ultimately clinically. So that if we’re wrong in the standard approach that a majority of the [cancer] field is taking – if that turns out not to be fruitful, and unfortunately it hasn’t been fruitful so far for glioblastoma so far, we don’t have all our eggs in one basket.
So, part of what this Pioneer Award is about is trying to approach this disease in a very different way than it’s than it’s been approached before, with the hope that doing something different and coming at the problem in a very different way may, ultimately, give us new, novel leads that will translate to something meaningful for our patients.
On the specific focus of his Pioneer Award*:
Scientists for decades have tried to model gliomas using patient-derived tumor cell lines cultured in lab dishes or human tumor cells implanted into the brains of mice. Both approaches have significant limitations.
“Traditional lab dish and animal models of gliomas just haven’t been sufficiently representative of clinical disease, and that’s been a big reason for the lack of success therapeutically,” says Dr. Fine.
Dr. Fine and his colleagues have instead been using advanced stem cell techniques to grow large clusters of functional and interconnected human brain cells, called cerebral organoids, in the laboratory. These cerebral organoids mimic many aspects of a normal 20-week old human fetal brain. This approach has been dubbed “mini-brains.”
Dr. Fine’s laboratory has developed technologies to use these cerebral organoids – or mini brains – to examine how individual patients’ gliomas grow and respond to therapies within a realistic biological environment.
Cerebral organoids, with their brain-like environments, have enabled Dr. Fine and colleagues to model brain cancers more accurately on the molecular level. They also have revealed some of the strange, emergent properties of brain cancers that aren’t visible in traditional models. “We can observe the physical networks of microtube structures that connect the individual tumor cells of some gliomas—networks that appear to have a profound impact on these tumors’ ability to resist chemotherapy and radiation,” Dr. Fine said.
With the new grant, Dr. Fine and his colleagues plan to enhance the realism of their organoid models by adding two vital components: blood vessels with key properties of cerebral vessels, and immune cells that normally reside in or can enter the brain.
Recent research from Dr. Fine and others has found that glioblastoma tumors—the most malignant gliomas—typically harbor genetic mutations that differ from patient to patient and offer no obvious common target for therapies. Part of Dr. Fine’s organoid-based research will therefore involve the development of personalized brain-cancer models using mini brains derived from the cells of patients, which may lead to the development of precision medicine treatment strategies. “We’ll be able to make hundreds of brain organoids for any given patient and use them to screen for drugs that can shrink that patient’s tumor,” Dr. Fine said.
More on Dr. Fine:
In addition to his role as Director of the Brain Tumor Center and Chief of the Division of Neuro-Oncology, Dr. Fine is also the Louis and Gertrude Feil Professor of Medicine at Weill Cornell Medicine and Associate Director for Translational Research at the institution’s Meyer Cancer Center and a neuro-oncologist at New York Presbyterian. He has more than 28 years of experience in both laboratory and clinical research as well as in the care of patients with brain tumors. He has cared for over 20,000 patients with brain and spinal cord tumors in his career, has conducted over 100 clinical trials, published over 250 papers and book chapters on brain tumors and has run a continuously operating translational genetic/molecular laboratory devoted to a better understanding of and better therapies for brain tumors for over two decades.
*Sourced from the Weil Cornell Medicine press release.