Why is it important to have a distinct program focusing on NETs?
These are so different from other cancers; they’re really a different entity and they require different therapies. Knowing how to select the initial treatments for a patient, then tailor those treatments, requires some expertise. Because NETs are not common, a community oncologist may only see a handful of cases ever. In addition, we are especially interested in meeting the long-term needs of these patients, and we have established a new NET survivorship program focused on addressing symptoms of cancer, side effects of treatment, nutrition, and mental health.

In recent decades it’s become increasingly clear that cancer is an incredibly complex disease. No two cancer types are exactly alike, no two patients are alike, and treating tumors involves attacking them from all angles. At Stanford, oncologists are tackling many sides of cancer research and patient care through innovative collaborations and programs. Two new programs in the Division of Oncology demonstrate this: the Neuroendocrine Tumor Program brings together professionals from many specialties to treat patients with these rare tumors; and the Phase I Clinical Research Program helps bring experimental new drugs to Stanford patients—while giving basic scientists vital research opportunities to study the drugs.

Recent conversations with the directors of the two programs convey what makes them unique and important.

To start out with, what are neuroendocrine tumors?
Neuroendocrine tumors, or NETs, are rare cancers that can originate in almost any part of the body. We most commonly see them in the gastrointestinal tract and lungs. They tend to be slower growing than other cancers; even patients with metastatic disease can live for many years. The incidence is very low—only about seven people per 100,000 are diagnosed each year in the U.S. But because many patients live for years with their disease, the prevalence is actually quite high. There are more people living with NETs in the U.S. than with esophageal, stomach, and pancreatic cancer combined.

Why is it important to have a distinct program focusing on NETs?
These are so different from other cancers; they’re really a different entity and they require different therapies. Knowing how to select the initial treatments for a patient, then tailor those treatments, requires some expertise. Because NETs are not common, a community oncologist may only see a handful of cases ever. In addition, we are especially interested in meeting the long-term needs of these patients, and we have established a new NET survivorship program focused on addressing symptoms of cancer, side effects of treatment, nutrition, and mental health.

What does managing the NET program at Stanford involve?
This disease requires complex coordination among many disciplines—medical oncology, surgical oncology, nuclear medicine, interventional radiology, endocrinology, cancer genetics, and psychiatry. So it’s really about pulling together the expertise to make sure patients get the best care. We see about 200 NET patients a year at Stanford, and they often travel long distances. We try to not only treat patients here, but partner with the patients’ oncologists back home.

Is the NET program involved in research as well as clinical care?
Yes. We have participated in many key clinical trials and other clinical research projects. This last year we participated in the study of a new drug called ¹⁷⁷Lu-Dotatate, which delivers radiation in a very targeted way to NETs; this is really the quintessential definition of a targeted therapy. The results of our work were published in the January 2017 issue of The New England Journal of Medicine, and the drug is now being reviewed by the FDA. It will very likely be the focus of future generations of studies. We want to know whether we can combine other treatments with ¹⁷⁷Lu-Dotatate, which patients respond best to the drug, and whether there are any long-term side effects. We are also looking for new diagnostic tests to better identify which patients may have more aggressive cancers so we can tailor selection of treatments.

What plans do you have for the NET program?
With so many new therapies for NETs, we are emphasizing patient and physician education. Three continuing medical education events in the next year will teach community physicians and other health care providers about NETs. We also host an annual NET patient education event. Lastly, we are thrilled to have received funding for a fellowship to train the next generation of NET specialists. Our first NET fellow will start in mid-2018. 

How did the Phase I program come about and what are its goals?
First of all, a phase I trial is when you’re testing a drug for the first time in humans; you’re trying to figure out safety, dosing, and which patient population to target. This is the key stage between preclinical development and clinical development. I was recruited to Stanford from the National Cancer Institute in 2015 and started the phase I clinical research program for patients with advanced solid tumors. The goals are to leverage the broad clinical and research expertise that exists at Stanford and to work with various stakeholders, including industry, to develop new therapies for cancer. The program is designed to facilitate development of promising anticancer therapies while ensuring the highest standards of patient safety.

What does the Phase I program at Stanford do to help ensure quality trials?
If researchers have a molecule that they’re interested in moving forward into phase I trials, we sit down with them and go through their information, we see if they need additional data, and we talk to them about what it will take to get a trial in place. We also help identify what resources will be needed to advance the research into the clinic. Then, we help design the clinical protocols and conduct the trials. Basically, we provide expertise that bench scientists may need to translate their findings.

You also work on phase I trials coming out of industry, right?
Yes. The majority of drug discovery and development happens in industry, where they’re identifying novel targets and developing new molecules for testing. Therefore, it is very important that we build that collaboration. It gives us access to cutting-edge molecules, and it creates opportunities for our patients to participate in clinical trials of these agents and for our scientists to conduct scientific studies with these molecules.

Why are phase I trials so important?
Phase I studies are at the interface of preclinical and clinical development. It’s basically where we make the decision about whether a new drug should be moved forward into later stage clinical development. A lot of drugs go all the way through clinical development and fail to work, so it’s important to have a strong phase I program that can help prioritize promising drugs early and expedite their development.

Why is Stanford a good place for phase I trials?
Stanford is very strong in basic and translational science. The sense of innovation here makes it a great place for phase I trials. Our Bay Area location is advantageous because we are able to interface easily with companies. The phase I program provides opportunities to translate the discoveries into the clinic and facilitate the development of new treatments.

Is there a phase I trial going on at Stanford right now that you’re particularly excited about?
Currently the phase I program is investigating a number of novel agents with a variety of mechanisms of action, ranging from immune therapies to genetically targeted agents. In collaboration with Loxo Oncology, our program is involved in the development of their new drug, larotrectinib, which targets solid tumors—including brain, breast, colorectal, thyroid, and lung cancers—with a particular genetic alteration. The drug has shown a 76 percent response rate in both adult and pediatric patients with metastatic tumors. The company is moving forward toward applying for drug approval, based in part on the results observed at Stanford. 

What plans do you have for the NET program?
With so many new therapies for NETs, we are emphasizing patient and physician education. Three continuing medical education events in the next year will teach community physicians and other health care providers about NETs. We also host an annual NET patient education event. Lastly, we are thrilled to have received funding for a fellowship to train the next generation of NET specialists. Our first NET fellow will start in mid-2018. 

How did the Phase I program come about and what are its goals?
First of all, a phase I trial is when you’re testing a drug for the first time in humans; you’re trying to figure out safety, dosing, and which patient population to target. This is the key stage between preclinical development and clinical development. I was recruited to Stanford from the National Cancer Institute in 2015 and started the phase I clinical research program for patients with advanced solid tumors. The goals are to leverage the broad clinical and research expertise that exists at Stanford and to work with various stakeholders, including industry, to develop new therapies for cancer. The program is designed to facilitate development of promising anticancer therapies while ensuring the highest standards of patient safety.

What does the Phase I program at Stanford do to help ensure quality trials?
If researchers have a molecule that they’re interested in moving forward into phase I trials, we sit down with them and go through their information, we see if they need additional data, and we talk to them about what it will take to get a trial in place. We also help identify what resources will be needed to advance the research into the clinic. Then, we help design the clinical protocols and conduct the trials. Basically, we provide expertise that bench scientists may need to translate their findings.

You also work on phase I trials coming out of industry, right?
Yes. The majority of drug discovery and development happens in industry, where they’re identifying novel targets and developing new molecules for testing. Therefore, it is very important that we build that collaboration. It gives us access to cutting-edge molecules, and it creates opportunities for our patients to participate in clinical trials of these agents and for our scientists to conduct scientific studies with these molecules.

Why are phase I trials so important?
Phase I studies are at the interface of preclinical and clinical development. It’s basically where we make the decision about whether a new drug should be moved forward into later stage clinical development. A lot of drugs go all the way through clinical development and fail to work, so it’s important to have a strong phase I program that can help prioritize promising drugs early and expedite their development.

Why is Stanford a good place for phase I trials?
Stanford is very strong in basic and translational science. The sense of innovation here makes it a great place for phase I trials. Our Bay Area location is advantageous because we are able to interface easily with companies. The phase I program provides opportunities to translate the discoveries into the clinic and facilitate the development of new treatments.

Is there a phase I trial going on at Stanford right now that you’re particularly excited about?
Currently the phase I program is investigating a number of novel agents with a variety of mechanisms of action, ranging from immune therapies to genetically targeted agents. In collaboration with Loxo Oncology, our program is involved in the development of their new drug, larotrectinib, which targets solid tumors—including brain, breast, colorectal, thyroid, and lung cancers—with a particular genetic alteration. The drug has shown a 76 percent response rate in both adult and pediatric patients with metastatic tumors. The company is moving forward toward applying for drug approval, based in part on the results observed at Stanford. 

In the United States and developing countries, most cases of chronic kidney disease (CKD) are seen in older individuals with risk factors like diabetes, high blood pressure, and cardiovascular disease. But in Sri Lanka—as well as small regions of southern India, Nicaragua, and El Salvador—the disease has been appearing in young, otherwise healthy, adults.

A similar outbreak of kidney diseases occurred in the 1950s and 1960s in the Balkans. Years later, researchers discovered that an herb growing in nearby fields was causing the cluster of cases. That historical case is why today’s scientists have a hunch that a toxin—in the groundwater, soil, or plants—may play a role in the current outbreaks.

Your kidneys, nestled in your lower back on either side of your spine, are the kind of organ system you don’t think about much until something goes wrong with them. If you’re healthy, your kidneys filter your blood to keep it clean, removing waste and producing urine. But if both kidneys stop doing this job, then you either need a new kidney—a transplant—or something else to mechanically filter your blood—dialysis.

The rate of kidney diseases in the United States and the rest of the developed world is on the rise, so research into how to prevent and treat these diseases is needed more than ever. At Stanford, a trio of early-career researchers exemplify the breadth of current nephrology research, and the energy and creativity needed to tackle some tough questions.

A Medical Mystery
Halfway around the world, in rural Sri Lanka, a mysterious kidney disease is killing farm workers. In the last decade, more than 20,000 deaths have been blamed on the disease, which is called chronic kidney disease of unknown etiology, or CKDu. Here in Palo Alto, nephrologist Shuchi Anand, MD, is on the hunt to find out what’s causing it and help spearhead new ways to screen and manage the thousands of patients who need ongoing care.

“The concern is that it’s a single toxin that’s causing the disease,” says Anand, who completed her fellowship in nephrology at Stanford in 2012 before joining the faculty as a nephrology instructor. “But at this point, we still don’t know.”

In the United States and developing countries, most cases of chronic kidney disease (CKD) are seen in older individuals with risk factors like diabetes, high blood pressure, and cardiovascular disease. But in Sri Lanka—as well as small regions of southern India, Nicaragua, and El Salvador—the disease has been appearing in young, otherwise healthy, adults.

A similar outbreak of kidney diseases occurred in the 1950s and 1960s in the Balkans. Years later, researchers discovered that an herb growing in nearby fields was causing the cluster of cases. That historical case is why today’s scientists have a hunch that a toxin—in the groundwater, soil, or plants—may play a role in the current outbreaks.

Anand, who has traveled to affected areas in Sri Lanka, is working on setting up a study to analyze what CKDu patients in Sri Lanka have been exposed to. So far, she and her colleagues have collected kidney biopsy data on about a hundred patients, with the goal of testing for infections, pesticides in their bodies, and other chemical levels.

“In the past, there’s been a lot of single-hypothesis research on CKDu,” says Anand. “There’s this new momentum toward creating collaborations that guide a more systematic approach, and Stanford has been a leading part of that effort.”

The results of their effort are still forthcoming, and the group hopes to eventually collect data on a total of 300 patients. Somewhere in the molecules contained in blood samples, they hope, is an answer.

Putting Numbers on a Disease
There are different ways that the kidneys can stop working. The blood vessels leading into the organs can become damaged, cysts can grow, stones can block the flow of urine, or the immune system can attack the kidneys. One subset of these diseases is dubbed glomerular diseases: They affect the tiny filters, called glomeruli, that help the kidneys function. But not all glomerular diseases are the same, and they have diverse causes—patients can develop them due to an autoimmune disease like lupus, after contracting an infection or taking certain drugs, or because of a genetic disease.

Michelle O’Shaughnessy, MD, an assistant professor of nephrology who moved to Stanford from Ireland in 2013, wants to sort out the differences between each type of glomerular disease, by quantifying the patients who contract them, how they contract them, and which treatments work.

“We see a huge spectrum of outcomes with glomerular disease,” says O’Shaughnessy. “Some patients do really well, while others do very poorly, and lots are in a spectrum between those two extremes.”

The challenge in figuring out which patients have which outcomes, she says, stems from the fact that there’s no national—or worldwide—registry of glomerular disease patients. As a result, studies tend to be small, focused only on patients within an individual hospital system. O’Shaughnessy is working on ways to mine large health record databases for information on patients with glomerular disease.

In 2017, O’Shaughnessy published the results of a large epidemiological study of more than 21,000 glomerular disease patients referred to the University of North Carolina, Chapel Hill, over a 30-year time span. She and collaborators found the rate of diabetes-related kidney disease to increase dramatically—accounting for nearly a fifth of all biopsy-proven glomerular disease by 2015.

“That’s really concerning because having diabetes and kidney disease portends a much poorer prognosis than having diabetes alone,” says O’Shaughnessy. “From a public health perspective, we as physicians need to be aware that this is increasing.”

Her next steps are to assemble a larger study of glomerular disease patients, following the course of disease beginning at diagnosis and including people who aren’t typically included in small controlled trials—those with other chronic diseases, and elderly people, for instance.

Targeting Transplants
Whether patients have glomerular disease or CKDu, they may need a kidney transplant if their kidney function deteriorates enough. Today, more than 100,000 people in the United States are on the waiting list for a kidney, yet only around 17,000 transplants are performed each year. While much of this lag is due to a shortage of organs, matching donors with recipients can also be a problem because patients can have antibodies that make them reject an organ. These antibodies react to proteins on the donor kidney called human leukocyte antigens, or HLAs.

“Our tissues are covered in these HLA proteins, and they’re kind of like a fingerprint,” explains Colin Lenihan, MD, an assistant professor of nephrology who—like O’Shaughnessy—hails from Ireland. If you’re exposed to these HLA molecules from someone else’s body—through pregnancy, blood transfusion, or a previous transplant—you can develop anti-HLA antibodies, a process called sensitization. However, some patients are sensitized but have no history of pregnancy, transfusion, or transplant, and it’s not clear why they have developed anti-HLA antibodies.

“Sensitization is a big problem,” Lenihan says. “Highly sensitized patients are less likely to find a compatible donor, and they also don’t tend to do as well after the transplant.” Some 20 percent of people waiting for a deceased donor kidney transplant, he says, are sensitized to more than 80 percent of all HLA types, limiting the organs they can receive.

Lenihan is studying whether the flu vaccine may play a role—he and his colleagues are testing levels of HLA antibodies in patients on the transplant waiting list at Stanford before and after they get a routine flu shot.

“The flu vaccine is really beneficial and saves lives, but there may be a subset of people who develop unwanted anti-HLA antibody after they get vaccinated,” Lenihan says. Of course, he admits, the study could also show no effect on HLAs from the flu vaccine, so it’s too early to make any changes to vaccine policies.

Anand, who has traveled to affected areas in Sri Lanka, is working on setting up a study to analyze what CKDu patients in Sri Lanka have been exposed to. So far, she and her colleagues have collected kidney biopsy data on about a hundred patients, with the goal of testing for infections, pesticides in their bodies, and other chemical levels.

“In the past, there’s been a lot of single-hypothesis research on CKDu,” says Anand. “There’s this new momentum toward creating collaborations that guide a more systematic approach, and Stanford has been a leading part of that effort.”

The results of their effort are still forthcoming, and the group hopes to eventually collect data on a total of 300 patients. Somewhere in the molecules contained in blood samples, they hope, is an answer.

Putting Numbers on a Disease
There are different ways that the kidneys can stop working. The blood vessels leading into the organs can become damaged, cysts can grow, stones can block the flow of urine, or the immune system can attack the kidneys. One subset of these diseases is dubbed glomerular diseases: They affect the tiny filters, called glomeruli, that help the kidneys function. But not all glomerular diseases are the same, and they have diverse causes—patients can develop them due to an autoimmune disease like lupus, after contracting an infection or taking certain drugs, or because of a genetic disease.

Michelle O’Shaughnessy, MD, an assistant professor of nephrology who moved to Stanford from Ireland in 2013, wants to sort out the differences between each type of glomerular disease, by quantifying the patients who contract them, how they contract them, and which treatments work.

“We see a huge spectrum of outcomes with glomerular disease,” says O’Shaughnessy. “Some patients do really well, while others do very poorly, and lots are in a spectrum between those two extremes.”

The challenge in figuring out which patients have which outcomes, she says, stems from the fact that there’s no national—or worldwide—registry of glomerular disease patients. As a result, studies tend to be small, focused only on patients within an individual hospital system. O’Shaughnessy is working on ways to mine large health record databases for information on patients with glomerular disease.

In 2017, O’Shaughnessy published the results of a large epidemiological study of more than 21,000 glomerular disease patients referred to the University of North Carolina, Chapel Hill, over a 30-year time span. She and collaborators found the rate of diabetes-related kidney disease to increase dramatically—accounting for nearly a fifth of all biopsy-proven glomerular disease by 2015.

“That’s really concerning because having diabetes and kidney disease portends a much poorer prognosis than having diabetes alone,” says O’Shaughnessy. “From a public health perspective, we as physicians need to be aware that this is increasing.”

Her next steps are to assemble a larger study of glomerular disease patients, following the course of disease beginning at diagnosis and including people who aren’t typically included in small controlled trials—those with other chronic diseases, and elderly people, for instance.

Targeting Transplants
Whether patients have glomerular disease or CKDu, they may need a kidney transplant if their kidney function deteriorates enough. Today, more than 100,000 people in the United States are on the waiting list for a kidney, yet only around 17,000 transplants are performed each year. While much of this lag is due to a shortage of organs, matching donors with recipients can also be a problem because patients can have antibodies that make them reject an organ. These antibodies react to proteins on the donor kidney called human leukocyte antigens, or HLAs.

“Our tissues are covered in these HLA proteins, and they’re kind of like a fingerprint,” explains Colin Lenihan, MD, an assistant professor of nephrology who—like O’Shaughnessy—hails from Ireland. If you’re exposed to these HLA molecules from someone else’s body—through pregnancy, blood transfusion, or a previous transplant—you can develop anti-HLA antibodies, a process called sensitization. However, some patients are sensitized but have no history of pregnancy, transfusion, or transplant, and it’s not clear why they have developed anti-HLA antibodies.

“Sensitization is a big problem,” Lenihan says. “Highly sensitized patients are less likely to find a compatible donor, and they also don’t tend to do as well after the transplant.” Some 20 percent of people waiting for a deceased donor kidney transplant, he says, are sensitized to more than 80 percent of all HLA types, limiting the organs they can receive.

Lenihan is studying whether the flu vaccine may play a role—he and his colleagues are testing levels of HLA antibodies in patients on the transplant waiting list at Stanford before and after they get a routine flu shot.

“The flu vaccine is really beneficial and saves lives, but there may be a subset of people who develop unwanted anti-HLA antibody after they get vaccinated,” Lenihan says. Of course, he admits, the study could also show no effect on HLAs from the flu vaccine, so it’s too early to make any changes to vaccine policies.