And yet, there’s hope

Anyone who knows Aruna Gambhir would never call her fragile. In her lifetime she’s earned three degrees, including an MBA; nursed family members through multiple cancer diagnoses; led a biotechnology company for more than a decade; and survived several health threats of her own. But on a recent quiet, midweek afternoon, as she leans gently against the back of a plush armchair, her petite frame dwarfed by the oversized cushions, her physical state is unmistakably delicate.

She has cancer. At 61, she’s fighting it for the third time.

Since November 2021, when doctors detected Gambhir’s latest bout of the disease, she has waged a biological battle against the condition, myelodysplastic syndrome, in which early forms of blood cells fail to mature into healthy cells: A bone marrow transplant wiped out and replaced faulty blood cells, and chemotherapy killed off any remaining cancerous cells. Despite all the treatments, her illness persisted, leaving her health in a tenuous balance.

While sitting in the light-flooded living room of her Portola Valley home, Gambhir tells her story. Cancer has evoked her family’s darkest days. She has lost her father, her brother, her son and her husband to the disease. She has assumed the role of a caregiver, even when it seemed daunting or unfair, even as she struggled for her own life.

Still, she holds onto hope — and it’s born from cells of the very tumor that took her son’s life, which are now being studied in a lab at Stanford Medicine. Gambhir hopes her family’s story will expedite progress in cancer research by bringing together government, biotechnology companies, and public and private research funders.

Her ultimate hope is that one day the biological perils that befell her family will be tamed and cancer will be transformed from a fatal illness to a disease that can be bested.

A biological secret

In 1982, when Gambhir was 22, her relationship with her father, Satya Bodapati, took an unexpected turn. He had been diagnosed with esophageal cancer, so, just after she graduated from the University of California, Berkeley, Gambhir started helping her mother care for him in Cupertino, California. Her father underwent surgery and radiation, and doctors deemed the treatment successful, noting that if he made it to the five-year mark without complications, he would be out of the woods. He did. “But, of course, right after the five-year mark, it came back,” Gambhir recalled. Shortly after the recurrence, he died.

She didn’t know it at the time, but it was her first exposure to what would become an unwelcome theme in her life: a seemingly endless recurrence of cancer in her family. Gambhir suffered two breast cancer diagnoses, one when she was 37 and another at 47. Then, in 2013, she and her husband, Sam Gambhir, MD, PhD, at the time professor and the chair of the radiology department at Stanford Medicine, were contending with their worst nightmare: Their son, Milan, had been diagnosed with one of the deadliest brain tumors, glioblastoma.

The early and aggressive cancers rose a red flag for their doctors, and the family was tested for and found to have a rare, inherited condition known as Li-Fraumeni syndrome, which essentially turns cancer into a trick candle.

First identified in 1969, Li-Fraumeni syndrome stems from a mutation in the gene p53, known for its role in tumor suppression. A functional p53 gene helps regulate cell growth and prompt repair to damaged DNA, among other functions, which keeps cells and tissue in tip-top shape. But when p53 is hampered, cells with damaged DNA stay damaged, and cell proliferation runs unchecked, drastically raising the risk for cancer. In other words, in people who have Li-Fraumeni, cancer can be extinguished, but its propensity to return is unrelenting.

A patient and a caregiver

Gambhir’s first cancer diagnosis came when Milan was a year old. Ten years later, she found out she had breast cancer for a second time. Her doctors caught it early and successfully removed it. Because Li-Fraumeni syndrome put her at serious risk for recurrence — and she had a gravely ill son — she eventually decided to have a double mastectomy and a full hysterectomy, a procedure in which the ovaries and uterus are surgically removed.

“When Milan was in a steady state, I took a few days to go into the hospital and get it taken care of. I didn’t want to be sick at the same time as Milan; I couldn’t care for him if I got sick again,” she said. “It’s one thing when a single person in the family is sick; it’s another when multiple people are ill. You have to pull together and essentially triage to care for the sickest person.”

For nearly two years, Aruna and Sam made Herculean efforts to save their son, bringing together a team of doctors and scientists at the top of their field to find a treatment that could help Milan. “But it wasn’t in time,” said Aruna Gambhir. Milan died at 16 on May 2, 2015.

Three years later, in 2018, the family was dealt another devastating blow, landing Aruna Gambhir back in the role of caregiver, this time for her husband. Sam Gambhir had been diagnosed with cancer. “I remember thinking, ‘No, how can it be? I’m the one with the mutation, I’m the one who should be next. Why is this happening?”

Sam Gambhir spent his career devising new technologies that could reveal signs of early diseases, particularly cancer. With an approach that balanced innovation and practicality, he had an array of curious and creative technologies brewing in his lab.

From a cancer-detecting smart toilet, to an “immunodiagnostics” technique, which repurposes the body’s immune cells to report on the presence of disease, his dedication to understanding and flagging signs of tumors earned him a reputation as a pioneer of early cancer detection.

Again, the Gambhirs fought with everything they had, rallying teams of world-renowned experts. He endured different assortments of drug cocktails. “We tried all sorts of innovative things, even a clinical trial of one, but the side effects left him in horrendous pain,” Gambhir said.

It was too much, and not enough. On July 18, 2020, seven years to the day of Milan’s tumor diagnosis, Sam Gambhir, beloved and venerated by his family and colleagues, died.

“To go through the experience of taking care of and losing your son — that’s the first sword through the heart. But to have to do so again, this time for your spouse, who everyone just loves — it was terrible,” she said.

Four months after her husband’s death, Gambhir learned of her third cancer diagnosis and returned to Stanford Hospital for care. While there, she had a visitor who ignited the first feeling of hope she’d had in a long time. Michelle Monje, MD, PhD, professor of neurology, came to tell her that less than a mile away in her Stanford Medicine lab, a new potential treatment for glioblastoma was growing in a petri dish. And it was thanks to Milan.

A devastating diagnosis

Until he was 14, Milan was the picture of health. Remarkably bright by any measure, with an impressive knack for science and math, he excelled in school, played guitar and spent his high school summers as an intern in Stanford Medicine research labs.

Gambhir remembers the day all of that changed. Milan was leaving the house when the water bottle he was holding slipped from his grip. “I didn’t think anything of it at the time, but that might have been the first indication that something wasn’t quite right,” she said.

That night, something more alarming happened. While eating dinner at the kitchen table, Milan started speaking incoherently. “He was talking gibberish — I thought he was joking around and I told him to stop,” Gambhir said. He eventually did, but when he recounted the experience to his mom, he said he couldn’t control it. “I was worried it was a stroke,” she said.

The Gambhirs took Milan to the emergency department, where doctors conducted a CT scan and an MRI. Sam Gambhir watched the image materialize on the monitor. “He knew exactly what it meant. He knew, in that moment, what was in store for our family — for Milan,” she said. Glioblastoma is one of the rarest and most aggressive forms of cancer, and its survival rate is dismally low. Most patients survive only about 14 months.

Milan survived 21 months. During that time, the Gambhir family tried desperately to rid Milan’s brain of the mass that threatened his life. Milan had two brain surgeries; underwent chemotherapy and radiation therapy; and received other treatments including withaferin A, a molecule isolated from the plant ashwagandha, an ingredient in ayurvedic medicine.

As a father, doctor, scientist and caregiver, Sam Gambhir was laser focused on finding a solution for Milan. He rallied a network of cancer doctors, some to provide direct care to Milan, and others, including Monje, to conduct research that involved obtaining samples of Milan’s brain tumor post-surgery and cultivating its cells in the lab to create glioblastoma tumor models.

Models grown from patients’ cells offer the best way to study tumors — they allow scientists to better understand the disease’s biological roots and devise targeted treatments. For Milan, Monje led that work, a task she usually delegates to others in her lab. “It was so important to get it right; I did it with my own hands,” she said.

From culture to clinical trial

Without identifying Milan as the donor, Monje shared his cells among researchers seeking clearer understandings of pediatric brain tumors and how to treat them. His cell culture became one that the Monje lab studied often. “His cells were a key enabler of what I think have been our most important discoveries over the last 10 years,” Monje said.

In particular, Monje and her lab showed how normal brain function, via neuron signaling, actually stimulates tumor growth.

A protein called neuroligin-3, which, under healthy circumstances, helps regulate neurons’ formation of new synapses, was a key culprit in fueling the growth of high-grade gliomas, a class of brain tumors that includes glioblastoma.

Through follow-up studies, Monje’s lab showed that, in mouse models of the disease, inhibiting neuroligin-3 halted growth of the tumor for several months. Between 2015 and 2019, Monje and her team continued to elucidate the underpinnings of neuron-tumor signaling and growth. Now, her team is in the early stages of conducting a clinical trial for a drug that could block neuroligin-3 in patients with the same type of tumor Milan had, as well as others like it.

Blocking neuroligin-3 alone won’t cure the cancer, Monje said, but it’s a big step. The five-year survival rate for glioblastoma is less than 1%, and if growth can be stalled early on, it could open the door for other treatments to attack the mass.

“Michelle came to me and explained the positive things that have come out of Milan’s cells,” said Gambhir. “It’s pretty amazing. She’s amazing. If Milan had to die — that something as promising as this could happen feels meaningful.”

“All of those studies were based on Milan’s cells,” Monje said. “My laboratory and Milan’s story have been so intertwined. He’s really contributed to our work.”

And he has inspired others to enter the field.

A powerful inspiration

In 2017, Michael Quezada, then a Stanford University freshman, had been researching breast cancer in a lab that happened to be one floor below Monje’s. He’d been wanting to switch his focus to brain tumors and asked Monje if he could join her team. “I’d known Milan and the Gambhirs since I was in preschool,” Quezada said. “He was my childhood best friend.” Witnessing Milan’s fight with cancer ignited a drive in Quezada to understand — and one day stop — the disease that took his friend’s life.

But he didn’t share that with Monje when he asked to join her lab. What’s more, Quezada had no idea that Monje had personally handled samples of Milan’s tumor.

Monje welcomed him into her lab. For three years, Quezada unknowingly worked with Milan’s cells, researching glioblastoma and other similar brain cancers. All the while, Monje mentored Milan’s best friend — and neither was the wiser.

That is, until, Quezada noticed a detail in a story, “And yet, you try,” published in Stanford Medicine magazine, which revealed Monje’s role in cultivating Milan’s cells. “I was in disbelief — it was honestly shocking,” he said.

As a high schooler with a terminally ill friend, Quezada remembers feeling helpless. “The only thing I could do was spend time with Milan and be there for him,” he said. “I felt like I was at the whim of the tumor. We all kind of were.”

After Milan’s death, Quezada thought about how he could have helped Milan more or done better in some way. “I constantly reflected on that,” he said. “I think when I found out that his cells were actually in the lab that I was working in, and that I had been working with his cells potentially for years, it let me feel like I was doing something — that I did something that was meaningful. It made me feel like I was a little bit less helpless.”

But it wasn’t until Quezada left to pursue an MD-PhD at Harvard that he finally told Monje of their shared connection. He had written a personal statement for his medical school application, and he shared the letter with her.

Quezada wrote about how watching Milan battle cancer set him on a mission, and it continues to be his driving force today — “to work at the forefront of patient care and the frontier of biomedical research, where we can make advancements so that fewer people find their dreams cut short.”

Quezada doesn’t often mention Milan’s death as his motivation to pursue medicine. It’s something he generally keeps private. But he’s glad he shared it with Monje. “I hope it meant something to her,” he said. “It meant something to me.”

A legacy that lives on

Milan always wanted to go to Stanford, Gambhir said. But now Milan’s name will be forever linked to Monje’s career through an endowed professorship, one of the highest honors given by the university. This fall she was named the Milan Gambhir Professor of Pediatric Neuro-Oncology.

“I’m enormously grateful,” Monje said. “It’s truly an honor, and there’s no name that I would rather carry forward through my work.”

“Now his name can live on in a different way,” Gambhir said. “It’s full circle.”

If her family’s story signals anything, it’s the need for a collective push to move the field forward, Gambhir said. “It will take all constituents. I’m the wife of a big-time researcher who couldn’t have done what he did without the private donations and support of his work alongside government grants. They all took a chance on his weird ideas — and those weird ideas became mainstream and changed the field.” Sam Gambhir’s ideas created a burgeoning field: early cancer detection and diagnostics. Now his wife carries the torch. “To one day be able to detect cancer so early and reliably that it’s, at worst, a chronic disease — that will be a big achievement.”

Editor’s note: Aruna Gambhir died on Nov. 29, 2023, at age 61.