Germ cell tumors begin in the cells that develop into sperm and eggs. Shown: cells from germ cell tumors
Cancer treatments often come with a trade-off: They beat back the disease, only to leave a host of side effects in its place. Some of those side effects – such as chemotherapy-related infertility – can be permanent and life changing.
Patients with germ cell tumors know this trade-off well. Such tumors, which begin in the cells that develop into sperm and eggs, primarily affect children and young adults, meaning patients who have not yet had children are faced with treatment decisions that could leave them unable to do so.
“The treatments we have are relatively effective in curing germ cell tumors, but they come with a whole host of serious side effects,” says Joanna Gell, a clinical instructor in the division of pediatric hematology and oncology at UCLA Mattel Children’s Hospital. “When you’re talking about treating a 15-year-old who wants to live for 70 more years, those side effects can have major impacts on the lives of these patients.”
Gell became interested in finding additional treatment options for germ cell tumors after helping care for a teenage girl with a hard-to-treat disease. Through an appointment to a clinical fellowship in the UCLA Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research’s training program, Gell now works with Amander Clark, a developmental biologist who studies germ cells, to research potential new treatment options.
Germ cell tumors most often develop in the testes and ovaries during embryonic development. However, germ cells that migrate incorrectly during development can lead to tumors in other parts of the body, including the spine, chest and brain.
“What makes this cancer really hard to study is that we think the disease begins in the womb and then remains latent until after birth or in young adults,” says Clark, a professor and chair of molecular cell and developmental biology in the College of Life Sciences at UCLA. “That means we can’t easily isolate or study the very earliest stages of the disease in patients.”
Joanna Gell, left, and Amander Clark in the lab
To overcome this hurdle, the pair developed a protocol for coaxing human embryonic stem cells, which can give rise to any cell type in the body, into becoming germ cell tumor cells. These stem cell-derived tumor cells can be examined to provide unprecedented insights into the genetics of the cancer.
The findings from this research, published in Stem Cell Research, could lead to the development of new treatments for germ cell tumors with fewer life-altering side effects.
Clark and Gell are now exploring whether their new protocol could be used to develop personalized therapies for germ cell tumors. They plan to reprogram skin cells from people with germ cell tumors into induced pluripotent stem cells and then coax those cells into becoming embryonic germ cells. This will give researchers the ability to re-create each patient’s tumor cells in the lab.
“By using induced pluripotent stem cells, we’ll now be able to understand the personalized events that occur in these early germ cells that could ultimately contribute to the formation of germ cell tumors,” says Clark. “If we know how the disease starts, we can develop treatments that force it to stop.”
Adoptive T cell immunotherapy typically involves collecting a type of mature white blood cells (the immune system cells) called T cells from patients with cancer. The T cells are genetically modified in the lab to identify and attack a specific type of cancer and then transfused back into the patient. When these genetically modified T cells are returned to the patient, they can more efficiently locate and eliminate cancer cells.
In clinical trials to date, adoptive T cell immunotherapy has shown great promise in treating late-stage tumors that are resistant to traditional cancer treatment methods like surgery, chemotherapy, and radiation. However, this method has limitations: Once transplanted back into patients, the population of modified T cells declines over time, which can lead to cancer recurrence.
Ribas’ clinical trial aims to overcome this limitation through a dual approach that creates both a short-term and long-term immune response. The method involves collecting both mature T cells and blood-forming stem cells from patients, genetically modifying them to target a common cancer tumor marker, and then returning the modified cells to the patients.
By adding blood-forming stem cells to the mature T cells that are traditionally deployed in adoptive T cell immunotherapies, this treatment addresses the issue of T cell population decline. Blood-forming stem cells give rise to all types of blood cells, including T cells, throughout a person’s life. Therefore, the engineered blood stem cells are able to boost the immune system with a continual supply of cancer-fighting T cells after the initial group of T cells has declined.
The result is a two-pronged attack on cancer: The modified mature T cells begin targeting cancer cells immediately while the blood-forming stem cells begin generating an ongoing supply of modified T cells that will carry on the fight, potentially preventing cancer recurrence.
The trial, which is funded by the California Institute for Regenerative Medicine, is currently open to people with tumors that have metastasized, meaning the cancer has spread to other parts of the body from its initial location. Potential participants must also have a specific tumor marker, called NY-ESO-1, and a specific type of immune system, called HLA-A2.1.
While the scope of this trial is highly specific, Ribas is optimistic that it will pave the way for future treatments for other cancers. “My hope is that the therapeutic principles and procedures developed in this trial will be applicable to a wider range of cancers in the future,” he said.
To learn more about this clinical trial, visit its page at clinicaltrials.gov. If you think you might be eligible to enroll, please contact Clinical Research Coordinator Justin Tran by email at firstname.lastname@example.org or by phone at 310-206-2090.
Drs. Ben Wu, Chia Soo, Kang Ting and Jin Hee Kwak at Kennedy Space Center
Early in the morning of July 3, 2017, 20 intrepid mice returned to Earth from the International Space Station aboard SpaceX’s Dragon capsule, splashing down in the Pacific Ocean off Baja, California. This landing marked the completion of a 28-hour journey back to Earth – and the first time live rodents have returned to the U.S. from the International Space Station.
Space is the ultimate testing ground for therapies to prevent bone loss because the microgravity environment leads to significant and rapid bone loss similar to the effects of osteoporosis and other bone-wasting diseases. These effects are common among returning astronauts, who, despite an extensive exercise routine, can lose up to 1.5 percent of their bone mass for each month spent in space.
Illustration of mice adapting to their space habitat on board the International Space Station. (Courtesy of the Center for the Advancement of Science in Space)
The experimental drug, developed at UCLA and based on a bone-building protein called NELL-1, works by stimulating specialized stem cells to create bone-building cells that generate new bone tissue. NELL-1 also inhibits bone-resorbing cells from destroying existing bone and has shown promising results in pre-clinical studies. If it proves effective in future clinical trials, the drug could prevent bone density loss during spaceflight and open new opportunities for humans to explore further into our galaxy.
It’s not only space travelers who could stand to benefit from NELL-1. After the age of 50, even earthbound humans begin losing their bone mass at an average rate of about 0.5 percent per year and up to 2 to 3 percent per year for post-menopausal women. This means that whether you’re planning to be the first person to reach Mars or simply hoping to remain physically active as you age, NELL-1 could one day change your life. Here’s an introduction to the interdisciplinary UCLA team behind the research:
Dr. Kang Ting discovered the NELL-1 protein’s role in stimulating bone growth while he was studying a rare condition that causes babies’ skulls to fuse too early. While NELL-1’s effect in these cases was detrimental, Ting and his colleague Dr. Ben Wu realized the protein could have a positive effect on people with bone injury or loss of bone mass– a group that includes older adults, people with traumatic bone injury, such as injured military service members, and of course astronauts. From there, the two researchers convened a team that would spend more than 18 years studying NELL-1’s effect on bone density.
Ting is enthusiastic about the potential of the drug:
“If this drug proves effective, it could really enhance the health and lives of so many people. That’s the exciting part – this discovery could shift the paradigm for treating osteoporosis in the future.”
In 2000, Dr. Ben Wu joined the UCLA faculty, connected with Ting and began working on translating his discovery into a therapy that could help patients experiencing bone loss. As a professor of engineering, Wu focused on developing molecules that could act as delivery vehicles for a therapeutic version of NELL-1. After 10 years of research on regenerating bone in targeted areas, such as in cases like spinal fusion or small fracture, the pair began to question whether NELL-1 could help patients with osteoporosis. This brought a new challenge, Dr. Wu explained:
“We had figured out how to get NELL-1 to stick to the scaffold of a damaged area, but with osteoporosis we needed to make it stick to everywhere that bone exists in the body.”
At the conclusion of an experiment process that Wu calls “decorating the NELL-1,” the pair landed on a molecule that they could attach to NELL-1. The molecule acts like a homing device that helps NELL-1 seek out and binds to bone tissue.
Principal investigator on the project, Dr. Chia Soo has designed and overseen studies of the NELL-1 drug from the beginning. Over the years, her role as research director for UCLA Operation Mend, a program that provides medical care for injured military service members, has provided her with a constant reminder of the need for NELL-1.
“One of the things we’re really focused on is how to get bone to grow better in patients who really need it,” said Soo. “Our patients who are injured during military service deserve better therapeutic options.”
Soo sees the space mission as a pivotal moment in the decades-long project:
“If NELL-1 is found to be successful in a microgravity environment, the chances of it being successful on earth would be significantly greater.”
Preparing to test the drug in space represented an exciting – and daunting – opportunity, and no one shouldered more responsibility for the complicated logistics of UCLA’s first animal study with NASA than project manager Dr. Jin Hee Kwak. Conducting animal research in space requires an unfathomable amount of preparation. Kwak spent two years coordinating with NASA and CASIS and running an average of 20 trials for every single aspect of the experiment – from developing a mechanism to keep the mice stationary during bone scans to finding the best surgical method to implant identity chips in the mice in order to prevent extrusion or migration of the chip over time. Now that the mice have returned alive and well, Kwak is getting a break from the logistics and a chance to reflect:
“Seeing that rocket blast off made me realize the power of this country and of teamwork. Pulling this off took a lot of people and coordination and seeing everyone working together towards one single goal was amazing.”
For more information on UCLA’s first rodent space travelers and the bone-building potential of NELL-1 read the news story.
Butler’s findings could lead to new medical treatments that help nerves regrow and reconnect – whether they’ve been severed by injury or damaged by the neuropathy that can occur in diabetes and other diseases.
As the nervous system forms during embryonic development, axons—threadlike projections that connect nerve cells—extend into the developing spinal cord. A special protein, called netrin1, was long thought to help axons find their way during development, in much the same way that a lighthouse guides a ship – by sending out a signal to orient it from afar. For decades, this explanation for how axons grow has been taught to neurobiology students across the globe.
Through years of research, Butler and her team found that netrin1 encourages axon growth in a rather different way. She has discovered that axons grow by following a pathway of netrin1 produced by stem cells in the nervous system. This pathway directs axons in their local environment, meaning the relationship between netrin1 and axons is more like that of a lattice and ivy – netrin1 guides axons by providing a pathway for them to stick to and grow on.
“Certain stem cells in the nervous system have an intrinsic capacity to lay down this growth path,” explained Butler, an associate professor of neurobiology in the David Geffen School of Medicine at UCLA. “These are huge effects. Netrin is a very powerful molecule that bundles and directs axon growth.” Butler published these findings recently in the journal Neuron.
Axons (green) project out from nuclei (light purple) of motor neuron cells. Credit: Laura Struzyna, Cullen Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia
This research has implications far beyond academia. With this discovery, researchers could develop new strategies using netrin1 to enhance the body’s natural nerve repair process.
Scientists are already exploring some promising approaches to nerve regeneration, such as artificially reproducing nerve channels, which are protective rings of tissue in which nerves grow. But a faster method is still desperately needed.
While damaged or severed nerves do have the capability to repair themselves, the process can be slow and painful — as wounded combat veterans know all too well. Furthermore, if muscles go too long without the stimulation of a nerve connection, a connection ultimately can become impossible, which could lead to amputation of a limb. In order for nerve regeneration to be successful, it must be quick – and netrin1 may be the secret to putting this process into overdrive.
“I have real hope that it may be possible to apply netrin therapeutically when we need to make injured nerves grow,” said Butler. “This will be important to test; can we coat nerve channels with netrin1 to help axons reform connects quickly enough to avoid permanent damage?”
Butler hopes the answer to this question is yes. If netrin1 can be used to successfully manipulate nerve growth, her discovery will not only changes textbooks, it would change nerve damage treatment options for millions of people worldwide.
On World Ovarian Cancer Day, celebrated this year on May 8, women fighting the disease have new reason to hope. This international awareness day was created to build solidarity among women with ovarian cancer.
For decades, researchers have been trying to unravel the mystery of why up to 85 percent of women who undergo the standard treatment (surgery and chemotherapy) for high-grade serous ovarian cancer – the most common subtype of ovarian cancer –experience recurrence of the disease.
In 2015, Dr. Memarzadeh, a professor of obstetrics and gynecology in the David Geffen School of Medicine at UCLA, uncovered and isolated the ovarian cancer stem cells that cause recurrence and identified a drug that she suspects could be combined with standard treatments to stop these cells in their tracks.
“We do a phenomenal job with surgery, removing as much of the tumor as we can see, and then we do standard chemotherapy, but the cancers still recur in most cases,” Memarzadeh said at the time. “If this combination of drugs proves effective, we may be able to improve outcomes for this devastating disease. I think it’s entirely feasible.”
In a study published last month, Dr. Memarzadeh and her team found that this combination therapy doubled the survival rate in animal models of ovarian cancer. The research team went on to test the therapy on 23 high-grade serous tumors created using patient samples collected during surgery. The combination therapy eliminated 50 percent of ovarian cancer tumors in the laboratory.
After noting this significant outcome, the team tested the combination therapy on tumors created in the lab using bladder, cervix, colon and lung cancer cells (all of which can have a similar resistance to chemotherapy) and found it to be effective at targeting a subset of those tumors, too.
In this Friday, Feb. 12, 2016, file photo, Lara, who is less than 3 months old and was born with microcephaly, is examined by a neurologist at the Pedro I hospital in Campina Grande, Paraiba state, Brazil. Felipe Dana/AP
Fourteen months after the Zika virus was declared a global health emergency, the long-term effects of the virus – and the neurological damage linked to it – are only now beginning to be understood. As Zika infections continue to spread, researchers around the world are working to expose the virus’ vulnerabilities. New research published by Genhong Cheng and Ben Novitch, investigators at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, has brought us one step closer to protecting those most at risk of Zika infection and its devastating outcomes.
Although most people who are infected with the mosquito-borne pathogen experience no symptoms at all, for some it brings consequences that will be felt for a lifetime. The infection can spread through mosquito bites and sexual contact and from mother to fetus. Thousands of women infected with the Zika virus have given birth to infants with microcephaly, a condition characterized by an abnormally small head and severely stunted brain development that can also cause seizures and breathing difficulties, as well as vision and hearing problems.
Cheng, a professor of microbiology, immunology and molecular genetics at the David Geffen School of Medicine at UCLA, and Novitch, a professor of neurobiology at the David Geffen School of Medicine at UCLA, and their colleagues, found that an enzyme produced naturally by the immune system can be manufactured into a compound that could ultimately help fight the disease. Their preclinical studies, published last month in the journal Immunity, suggest that the compound could both suppress Zika infection and reduce the neurological damage linked to the virus.
Previous research published by Cheng in 2013 found that this enzyme, called 25-hydroxycholestrol, or 25HC, can protect cells against a broad range of viruses including hepatitis C, Ebola and HIV. While the body doesn’t typically produce enough 25HC to combat these and other aggressive viruses, the administration of a synthetically produced version does the trick, according to animal studies.
Recently, Cheng and his colleagues tested the enzyme’s effects on mini brain organoids, which are small sections of simplified, three-dimensional brain tissue engineered in the lab from human stem cells. They found that the enzyme blocked the virus and preserved normal brain cell formation in the organoids, which demonstrates the enzyme’s potential for treating humans with Zika. The research team will continue to study 25HC in the hopes of developing a more effective drug that can block Zika and other mosquito-borne viruses.