TAG: "Cancer"

Combined chemotherapy, immunotherapy shows promise for prostate cancer

Achieves near complete remission in mouse models of advanced prostate cancer.

By Heather Buschman, UC San Diego

Chemotherapy can be very effective against small prostate tumors. Larger prostate tumors, however, accumulate cells that suppress the body’s immune response, allowing the cancer to grow despite treatment. Researchers at the UC San Diego School of Medicine now find that blocking or removing these immune-suppressing cells allows a special type of chemotherapy — and the immune cells it activates — to destroy prostate tumors. This novel combination therapy, termed chemoimmunotherapy, achieved near complete remission in mouse models of advanced prostate cancer.

The study is published today (April 29) in Nature.

Advanced or metastatic prostate cancer does not typically respond to chemotherapy. Prostate cancers also fail to respond to a promising new type of immunotherapy drugs, called checkpoint inhibitors, which disable cancer cells’ cloaking mechanism so that a person’s own immune system can better fight the tumor. This specific resistance is likely due in part to immunosuppressive B cells, which are more common in larger prostate tumors in mice, as well as in advanced and metastatic prostate cancer in humans. As the name suggests, these cells keep the immune system at bay, rendering most therapies ineffective and allowing malignant tumors to grow unchecked.

In this study, researchers worked with three different mouse models of advanced prostate cancer. All three models were resistant to low doses of the chemotherapy drug oxaliplatin, which has the unique ability to activate cancer-killing immune cells. But when the researchers blocked the development or function of immunosuppressive B cells or removed them entirely before treating the mice with low-dose oxaliplatin, the prostate tumors were almost completely destroyed by the mice’s own immune cells. The team got similar results when low-dose oxaliplatin was combined with a checkpoint inhibitor.

“The presence of such B cells in human prostate cancer calls for clinical testing of this novel therapeutic approach,” said Shabnam Shalapour, Ph.D., postdoctoral researcher and first author of the study.

Prostate cancer is the second leading cause of cancer-related death in American men. About one in seven men will be diagnosed with prostate cancer during their lifetimes.

“In addition to prostate cancer, similar immunosuppressive B cells can be detected in other human cancers,” said senior author Michael Karin, Ph.D., Distinguished Professor of Pharmacology and Pathology at UC San Diego. “This indicates that B cell-mediated immunosuppression might be the reason several other cancers are also unresponsive to checkpoint inhibitors, raising the hope that chemoimmunotherapy will have broader applications for many cancer types.”

Study co-authors include Joan Font-Burgada, Giuseppe Di Caro, Zhenyu Zhong, Elsa Sanchez-Lopez, Debanjan Dhar, Massimo Ammirante, Amy Strasner, Donna E. Hansel, Christina Jamieson, and Christopher J. Kane, UC San Diego; Gerald Willimsky, Charite-Medical University of Berlin; Tobias Klatte, Peter Birner, and Lukas Kenner, Medical University of Vienna.

This research was funded, in part, by the National Institutes of Health (grants CA127923 and AI043477), California Institute for Regenerative Medicine, German Research Foundation, Genome Research-Austria and Cancer Research Institute.

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UC Irvine oncologist receives NIH grant to study leukemia cell mutation

Richard Van Etten’s research targets gene that may hold a key to killing B-ALL cells.

Richard Van Etten, UC Irvine

UC Irvine cancer specialist Richard Van Etten, M.D., Ph.D., has received a $2.7 million grant from the National Institutes for Health to continue his research into understanding and exploiting a genetic mutation that may be a key to treating a common and aggressive form of leukemia.

“B-cell acute lymphoblastic leukemia is a cancer of immune cells that has a high risk for relapse and poor overall survival,” said Van Etten, professor of medicine, Division of Hematology/Oncology, UC Irvine School of Medicine and director of the UC Irvine Health Chao Family Comprehensive Cancer Center. “Mutations in a gene known as Ikaros have been shown to cause resistance to chemotherapy drugs. Our studies are aimed at understanding the biological role of Ikaros in the development of B-ALL and its response to therapy.”

Van Etten said his study of Ikaros-deficient B-ALL in mice with collaborator Katia Georgopoulos, Ph.D., at Massachusetts General Hospital in Boston, has identified a novel pathway that may point the way to improved treatments and possible cure of this devastating leukemia.

B-cell acute lymphocytic leukemia is a fast-growing type blood cancer in which too many immature white blood cells, known as B-cell lymphoblasts, are found in the bone marrow and blood. It is the most common type of acute lymphoblastic leukemia (ALL), according to the National Cancer Institute. Annually, more than 50,000 cases of all types of leukemia are diagnosed and nearly 25,000 people die of the disease.

Van Etten is internationally recognized for his groundbreaking research on chronic myeloid leukemia and other hematological malignancies. Prior to coming to UC Irvine in 2013, Van Etten directed a highly successful research laboratory at Tufts Medical Center, funded by the National Institutes of Health and the Leukemia & Lymphoma Society, at the Molecular Oncology Research Institute.

The UC Irvine Health Chao Family Comprehensive Cancer Center is one of only 41 National Cancer Institute-designated comprehensive cancer centers in the U.S. and the only one in Orange County. The institute’s highest designation, comprehensive cancer centers conduct transformative cancer research and clinical trials, provide patients with leading treatments and prevention education, and set national cancer care guidelines. All five UC medical centers have NCI-designated comprehensive cancer centers.

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SPARK Gala returns to support cancer research and care

34th annual UC San Diego Moores Cancer Center gala benefits ‘bench-to-bedside’ research.

Actress and singer Megan Hilty will perform at the 2015 SPARK Gala.

By Kristin Luciani, UC San Diego

San Diego community members, physicians and cancer survivors will come together Saturday, April 25, at the Grand Del Mar for SPARK Gala, an evening to “ignite the fight against cancer.” The gala will feature a cocktail reception, dinner, auction and special performance by actress and singer Megan Hilty, who made her Broadway debut as Glinda in “Wicked.” Proceeds from the event will benefit patient care and research at UC San Diego Moores Cancer Center, including helping to launch a new Cancer Immunotherapy Program.

“We are proud to have exceptional physicians, researchers and staff who are committed to delivering the best possible care for patients with cancer,” said Chancellor Pradeep K. Khosla. “With support from generous donors, we continue to make great progress in understanding this disease in all of its forms and developing effective therapies.”

SPARK, the 34th annual Moores Cancer Center gala, is an opportunity for the community to recognize the advances made in the fight against cancer while garnering support to spur new discoveries. Last year, the event raised more than $5 million for the cancer center through the generosity of guests as well as matching gifts.

Wanda and Cam Garner, co-chairs of the gala, know firsthand how destructive the disease can be. Cancer has touched four generations of Cam’s family, primarily in the form of leukemia and lymphoma. His father died at age 49, when Cam was 17, and his sister died at age 39. His brother and mother also died of cancer-related causes, and his niece has been diagnosed.

“We want to be sure that San Diego has a world-class cancer center, with the best doctors and researchers, so that no one here needs to leave in order to receive the highest quality of care,” said Wanda and Cam Garner.

This year marks the 10th anniversary of Moores Cancer Center. Part of UC San Diego Health System, Moores Cancer Center is one of just 41 National Cancer Institute-designated Comprehensive Cancer Centers in the country — and the only one in the San Diego region — that is leading a broad range of research initiatives and patient-centered programs to improve prevention, detection and care. In addition, in 2016, UC San Diego Health System will open the new Jacobs Medical Center, which will house the Pauline and Stanley Foster Pavilion for Cancer Care, a state-of-the-art in-patient facility to meet the projected needs of the region as San Diego’s population grows and ages. Designed with input from cancer patients and families, the pavilion will provide the latest in technology for clinical care.

Proceeds from the SPARK Gala will help launch the new Cancer Immunotherapy Program at UC San Diego Moores Cancer Center. The funds will make possible groundbreaking immunotherapy clinical trials with novel drugs and vaccines as well as an experimental treatment in which patients’ own immune cells are genetically engineered to fight their cancer. The Cancer Immunotherapy Program at Moores Cancer Center is unique to only a handful of academic medical centers around the country.

“Immunotherapy is extremely precise and is transforming outcomes in ways never thought possible,” said Dr. Scott Lippman, director of Moores Cancer Center. “Our team, led by world-renowned physician-scientists Drs. Ezra Cohen and Tom Kipps, has already developed and activated several key clinical trials that include the exploration of novel immune checkpoint inhibitors. These paradigm-shifting studies show remarkable promise in patients battling cancers even when resistant to traditional therapies. In the next year, we will dramatically expand the scope of this program to include immune cellular therapy, such as adaptive T-cell transfer.”

Guests at the 2015 SPARK Gala will enjoy a musical performance by Megan Hilty. Since making her Broadway debut as Glinda in “Wicked,” Hilty has performed in a broad range of roles, from singing with the New York Philharmonic to starring in NBC’s musical drama, “Smash” and television comedy, “Sean Saves the World.”

The gala will begin at 6 p.m. with a cocktail reception, followed by dinner, auction and performance by Hilty. Individual tickets are $600 and sponsorships are available. For event details and reservations, visit sparkgala or call (858) 534-4289.

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Immunotherapy drug shows success in treating advanced lung cancer

UCLA researchers say study also will help ID which people could respond best to treatment.

Edward Garon, UCLA

By Reggie Kumar, UCLA

In what is thought to be the largest study to date using immunotherapy to treat lung cancer, UCLA researchers have found that the drug pembrolizumab (Keytruda), recently approved by the U.S. Food and Drug Administration to treat some melanoma patients, is safe and effective in arresting tumor growth in people with advanced non-small cell lung cancer.

Approximately 25 percent of patients’ tumors had high levels of the protein PD-L1, and the study found that they were the people most likely to have the best outcomes. The research was the first validation of PD-L1 expression as a marker of how patients will respond to the drug.

“These results have the potential to substantively change the way that lung cancer is treated,” said Dr. Edward Garon, a member of UCLA’s Jonsson Comprehensive Cancer Center and lead author of the study. “The effectiveness of pembrolizumab in treating patients with non-small cell lung cancer and the prolonged duration of their responses is quite exciting.”

The study was published online in the New England Journal of Medicine April 19, coinciding with a presentation of the findings by Garon at the American Association for Cancer Research annual meeting.

Pembrolizumab is an antibody that targets a protein expressed by immune cells called PD-1. In the body, PD-1 acts as an immune checkpoint inhibitor, turning down the immune system’s T cells that otherwise could attack cancer cells as invaders. Pembrolizumab takes the brakes off the immune system and allows T cells to identify and attack cancer cells.

The FDA granted “breakthrough therapy” designation to pembrolizumab for non-small cell lung cancer in October 2014 under its Accelerated Approval program. Last September, the drug was approved by the FDA to treat people with late-stage melanoma.

The nearly three-year clinical trial involved 495 participants, including nearly 100 at UCLA. The overall response rate — the percentage of people in whom tumors were substantially reduced in size — was 19 percent, and the average duration of response in those who responded exceeded one year, regardless of the level of PD-L1 expression.

In addition, less than 10 percent of patients experienced severe (grade 3 or greater) drug-related adverse events, a rate much lower than what is typically seen with traditional chemotherapies.

Approximately one-quarter of those screened in the trial had PD-L1 expression in at least half of their tumor cells. Among them, the overall response rate was nearly 50 percent. Although previous data suggested that clinical outcomes with this class of drugs could be associated with the level of PD-L1 expression, this study was the first to validate this finding in a scientifically rigorous way.

The median duration of survival in the high PD-L1 expression group of patients could not be reported because most of the patients are still alive.

“Although we continue working to refine our selection of patients for this type of therapy, the identification of a population of patients who are likely to have such a good outcome is potentially game-changing for this group,” said Garon, who also co-authored a study on tumor mutations and immunotherapy that was published this month in the journal Science. That research aimed to further refine patient selection factors.

Lung cancer is now the leading cause of death worldwide, and the American Lung Association estimates that more than 158,000 in the U.S. will die from the disease this year alone. Garon said he hopes that the findings will encourage the FDA to approve Keytruda for the treatment of non-small cell lung cancer in those people who are most likely to benefit.

“Neither the drug nor the PD-L1 biomarker test is approved for use at this time, but if I had a patient whose tumor had PD-L1 expression in at least half of their cancer cells and pembrolizumab was available, I would find the drug to be a compelling treatment option for the patient,” Garon said.

One survivor’s story

Stephen Burrin, now 71, was always health conscious and an avid runner. After he was first diagnosed with throat cancer, in 2002, he underwent surgery to remove the tumor and had extensive chemotherapy and radiation treatments. Fortunately, the treatment was a success, and Burrin was cured.

But eight years later, Burrin suffered a series of devastating diagnoses. Doctors initially discovered a new cancerous tumor that was so large it nearly filled the two upper lobes of his lungs. The following year, two additional tumors were found in the right lower lobe of his lung and in his thigh. Finally, in 2012, a CT scan revealed more than 20 additional tumors in both lower lobes of the lungs.

Instead of opting for more chemotherapy and surgery, Burrin decided to get a second opinion at UCLA, where he met with Dr. Jonathan Goldman, a member of the Jonsson Cancer Center and co-author of the New England Journal research. Goldman told Burrin about the recent success of pembrolizumab to treat melanoma, and explained that Garon’s clinical trial was open to lung cancer patients.

Burrin enrolled in the trial and, after he took pembrolizumab for several months, his tumor volume was substantially reduced.

“It’s a miracle I’m alive,” Burrin said. “This immunotherapy has been unbelievably successful for me, and the side effects have been very minor.”

The drug has continued to prevent Burrin’s cancer from worsening. He has been able to renew his passion for running, and in October he completed the Manhattan Beach 10K Run. He also has been able to realize two other meaningful milestones: holding his newborn grandson and celebrating his 40th wedding anniversary in Hawaii.

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Simple dietary change may have big impact on public health

Overnight fasting may reduce breast cancer risk in women.

By Yadira Galindo, UC San Diego

A decrease in the amount of time spent eating and an increase in overnight fasting reduces glucose levels and may reduce the risk of breast cancer among women, report UC San Diego School of Medicine researchers in the journal Cancer Epidemiology, Biomarkers & Prevention.

The findings were presented at the American Association of Cancer Research’s annual meeting in Philadelphia.

“Increasing the duration of overnight fasting could be a novel strategy to reduce the risk of developing breast cancer,” said Catherine Marinac, UC San Diego doctoral candidate and first author on the paper. “This is a simple dietary change that we believe most women can understand and adopt. It may have a big impact on public health without requiring complicated counting of calories or nutrients.”

Women who fasted for longer periods of time overnight had significantly better control over blood glucose concentrations. The data show that each three-hour increase in nighttime fasting was associated with a 4 percent lower postprandial glucose level, regardless of how much women ate.

“The dietary advice for cancer prevention usually focuses on limiting consumption of red meat, alcohol and refined grains while increasing plant-based foods,” said co-author Ruth Patterson, Ph.D., UC San Diego Moores Cancer Center associate director for population sciences and program leader of the cancer prevention program. “New evidence suggests that when and how often people eat can also play a role in cancer risk.”

Women in the study reported eating five times per day with a mean nighttime fasting of 12 hours. Those who reported longer fast durations also indicated they consumed fewer calories per day, ate fewer calories after 10 p.m. and had fewer eating episodes.

Researchers recommend large-scale clinical trials to confirm that nighttime fasting results in favorable changes to biomarkers of glycemic control and breast cancer risk.

Co-authors include Loki Natarajan, Dorothy Sears and Sheri Hartman of UC San Diego; and Linda Gallo and Elva Arredondo of San Diego State University.

Funding for this research came, in part, from the National Cancer Institute-sponsored Ruth L. Kirschstein National Research Service Award (1F31CA183125-01A1), the NCI Centers for Transdisciplinary Research on Energetics and Cancer (1U54CA155435-01) and philanthropic support from Ms. Carol Vassiliadis and family.

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Comprehensive genomic tumor profiing comes to UC Davis

Cancer center enters collaboration with Foundation Medicine.

By Dorsey Griffith, UC Davis

The UC Davis Comprehensive Cancer Center and the Department of Pathology and Laboratory Medicine have entered into a collaboration with Foundation Medicine, a leading molecular information company. The collaboration brings comprehensive genomic profiling into standard of care at UC Davis, allowing physicians to prescribe the most effective, targeted cancer treatments to patients based on the genomic information specific to each individual’s cancer.

UC Davis will leverage Foundation Medicine’s molecular information to drive targeted programs, research initiatives and clinical trials that have the potential to improve patient outcomes. UC Davis will contribute outcomes data generated from these efforts to incorporate into Foundation Medicine’s molecular information knowledge base, FoundationCORE, to provide the broader oncology and pathology communities with information to help inform treatment decisions for other patients.

“Foundation Medicine is the commercial leader in comprehensive genomic profiling of cancerous tumors,” said Ralph de Vere White, distinguished professor of urology and director of the UC Davis Comprehensive Cancer Center. “Combined with our basic, clinical and translational cancer research expertise, we hope to ultimately reduce the burden of advanced cancer in this region.”

Lydia Pleotis Howell, chair of the UC Davis Department of Pathology and Laboratory Medicine, expressed enthusiasm about the collaborative approach with Foundation Medicine, which will go beyond genomic testing of tumors.

“The data-sharing aspect of this relationship will enhance the academic work at UC Davis Health System and can be a model of collaboration between academia and industry,” she said.

Advances in genomics have led to the development of many new therapies designed to target specific gene alterations typically associated with certain tumor types, but may also be found across other tumor types. These discoveries are the basis of a new direction in cancer care in which specific genomic alterations that cause cancer growth are identified in an individual’s tumor, and patients are treated with drugs, or a combination of drugs, designed to target those lesions, sparing the patient treatments unlikely to have a therapeutic benefit.

“Clinical research centers across the country are recognizing the benefits of comprehensive genomic profiling and the difficulty of assembling the technology and systems to do this with the necessary degree of accuracy,” said Dave Daly, chief commercial officer of Foundation Medicine. “We are looking forward to providing this valuable genomic information to the UC Davis Comprehensive Cancer Center as they continually seek to optimize patient care.”

Foundation Medicine uses comprehensive genomic profiling to analyze clinical specimens to detect clinically relevant alterations in hundreds of cancer-related genes. The company then combines the genomic data with the latest scientific and medical information, including targeted therapeutic agents and open clinical trials. The final clinical report allows physicians to match each patient to potential treatment options based on the genomic profile of the patient’s unique cancer. An estimated 85 percent of samples sent to Foundation Medicine have at least one clinically relevant genomic alteration. Foundation Medicine also offers assistance to patients with cancer and their families seeking access to prescribed targeted therapies through a program called FoundationOne CareLine, as well as a financial assistance program, FoundationACCESS, to address certain financial, access and claim issues.

UC Davis intends to collaborate with Foundation Medicine to develop a genomic tumor board, in which individual patient cases are discussed and oncologists at the Cancer Center determine the best therapeutic options based on genomic profiles. In addition, the two leaders are also discussing grand rounds lectures, medical school courses on the role of molecular-targeted treatments in cancer care, as well as other continued medical educational opportunities. In addition, because insurance coverage for certain targeted therapies can require an exhaustive authorization process,  de Vere White will work with the company and insurance payers – including Medi-Cal, the state’s Medicaid program – to develop an agreed-upon protocol that would streamline clinical trial enrollment and enable coverage of patients for testing and treatment with FDA-approved therapies and molecularly-driven drug trials.

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Keytuba shown to improve response to tumors of people with advanced melanoma

UCLA-led study finds immunotherapy drug performs better than current standard of care.

Antoni Ribas, UCLA

By Reggie Kumar, UCLA

An international team of researchers led by doctors at UCLA has found that pembrolizumab (Keytruda) was more effective in treating advanced melanoma than the current standard of care treatment, ipilimumab (Yervoy). The study, published online today (April 19) by the New England Journal of Medicine, found that pembrolizumab improved tumor response and duration of response, and extended the lives of people with melanoma — and with less severe side effects — than ipilimumab.

Developed under the leadership of Dr. Antoni Ribas, a member of the UCLA Jonsson Comprehensive Cancer Center and UCLA professor of hematology and oncology, Keytruda has signaled a paradigm shift in the way melanoma is treated. The drug is an antibody that blocks a protein called PD-1 that is expressed by immune cells. PD-1 puts the immune system’s brakes on, keeping T cells from recognizing and attacking cancer cells.

Ribas is scheduled to speak about the findings at 5:30 a.m. PT today at the annual meeting of the American Association for Cancer Research.

Ipilimumab is the current standard first-line therapy for patients with metastatic melanoma. Like Keytruda, it works by binding to another immune break on a T cell, called CTLA-4. Pembrolizumab is approved as second-line therapy for people with metastatic melanoma whose tumors no longer respond to ipilimumab or BRAF inhibitors.

“This is the first clinical trial to compare head-to-head two immune checkpoint inhibitors, which unleash and immune response against the cancer,” Ribas said. “We are delighted that we found that pembrolizumab produces better responses and survival rates than ipilimumab as a first-line therapy.”

In the phase three trial, investigators in 16 countries treated 834 people who had metastatic melanoma with either pembrolizumab or ipilimumab, which were assigned randomly. The researchers assessed treatment responses by two criteria: the length of time before a patient’s cancer worsened (also known as progression-free survival) and overall survival rate. Ribas also assessed patients’ overall response rate to treatment and safety.

Study results showed that after six months, 45 percent of those taking pembrolizumab compared to 26 percent for ipilimumab responded to therapy. Overall survival at one year for patients who received pembrolizumab was 74 and 68 percent in two study groups, compared with 58 percent for those who received ipilimumab.

In addition, the tumor response rate was 33 percent for people who took pembrolizumab versus 12 percent for ipilimumab. Adverse side events were also less frequent for patients receiving pembrolizumab (12 percent) than for those taking ipilimumab (20 percent).

With these findings, Ribas said he hopes the FDA will designate pembrolizumab as a first-line therapy for metastatic melanoma.

“This is a new milestone in advancing immune therapies for cancer,” Ribas said. “Our thinking about how to use the immune system to treat cancer began to change dramatically two decades ago, when the focus shifted from turning on the immune system to releasing the breaks that limit immune responses to cancer. This led to the development of both ipilimumab and pembrolizumab, and now we have clear evidence that this approach helps improve the lives of people with advanced melanoma.”

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Research suggests strategy to prevent cancer relapse

Angiogenesis inhibitors undermined by immune cells, says study.

By Pete Farley, UC San Francisco

Angiogenesis inhibitors — a widely used class of cancer drugs designed to shrink tumors by preventing them from forming new blood vessels — often work in the short term, but usually become ineffective within months. Now, a team led by UC San Francisco scientists has discovered a possible reason, one that could lead to a way to address the problem and prevent cancer relapse.

Working with laboratory models of pancreatic and breast cancer, the scientists found that myeloid cells, which originate in bone marrow and are part of the body’s first-line of defense — the so-called “innate” immune system — at first work in concert with the therapy but then switch roles and undermine it.

As reported in today’s (April 16) online issue of Cell Reports, the researchers, under the direction of senior investigator Gabriele Bergers, Ph.D., UCSF professor of neurological surgery, and first author Lee B. Rivera, Ph.D., a UCSF postdoctoral scholar in the Bergers laboratory, also identified a potential way to stop myeloid cells from sabotaging the therapy and prevent relapse. The key to the discovery, said Bergers, lies in the dual nature of myeloid cells, which exist in two basic states.

In one state, myeloid cells are immunity-enhancing and angiostatic – that is, they prevent the formation of new blood vessels. “This is important in the early stages of wound healing,” she explained, “when they need to be immune-stimulatory and attack when bacteria, for example, are invading.” But during the later stages of healing, “they need to switch to their other state, in which they are angiogenic” — generating new blood vessels — “and immune-suppressive, because new blood vessels need to form as part of tissue repair, and you don’t want cells around that are in attack mode.”

During anti-angiogenic therapy, said Bergers, the Neill H. and Linda S. Brownstein Endowed Chair in Brain Tumor Research and a member of the UCSF Helen Diller Family Comprehensive Cancer Center, “the tumor hijacks the second stage of the natural process we see in wound healing for its own advantage. But we have learned that we can also manipulate this process to make therapy more effective.”

Angiogenesis inhibitors approved for clinical use, which include bevacizumab (Avastin), sunitinib (Sutent), and everolimus (Afinitor), work by blocking the vascular endothelial growth factor (VEGF) signaling pathway, which prevents the tumor from forming new blood vessels, thereby shrinking it.

The researchers found that during the initial phase of therapy, VEGF inhibition stimulates myeloid cells within the tumor to release the signaling protein CXCL14, which is angiostatic and stimulates immunity. During this phase, myeloid cells complement the therapy to prevent the creation of new blood vessels, and the tumor shrinks.

But then — probably in response to reduced oxygen flow within the tumor — myeloid cells switch to their opposite state “and become real bad guys,” said Bergers. At this stage the cells activate the PI3-kinase (PI3K) signaling pathway, which neutralizes CXCL14 and promotes angiogenesis and tumor growth.

“Once the PI3K pathway is activated, therapy becomes ineffective, and you have relapse,” she said.

In breast cancer, Bergers noted, anti-VEGF therapy is not very effective to begin with. “This tells us why,” she said. “In a laboratory model of breast cancer, about 45 percent of myeloid cells are already activated, so the cancer just ignores the therapy.”

The researchers found that targeting specific innate immune cells within the tumor did not reverse the negative effects of PI3K activation. Eliminating macrophages – one type of white blood cell – resulted in an increase in neutrophils, another type of white blood cell. But eliminating neutrophils brought on an increase in macrophages. This so-called myeloid-cell oscillation maintained the tumor’s resistance to the therapy.

Instead, said Bergers, “we found that what you need to do is target the central signaling node, which is PI3K.” Ultimately, the researchers demonstrated that combining a PI3K inhibitor with anti-VEGF therapy prevented relapse and significantly increased survival in a mouse model of pancreatic neuroendocrine tumor.

Bergers noted that the discovery potentially gives physicians a way to determine how effective anti-VEGF therapy might be in individual patients, as well as to monitor the course of therapy. “In some new patients, we could test to determine how many myeloid cells in the tumor were already activated, which could tell us to what extent the tumor would still be responsive to anti-VEGF therapy,” she said.

In patients undergoing therapy, “we could take advantage of the fact that myeloid cells occur not only in the tumor, but also in the blood,” said Bergers. “A simple blood test would give us a non-invasive biomarker to check on the state of myeloid activation. Right now, one of the major issues in anti-VEGF therapy is that there are no biomarkers for response and relapse.”

Co-authors of the study are Emily Bergsland, M.D., the Ernest Rosenbaum, M.D., Endowed Chair in Medical Oncology at UCSF; David Meyronet, M.D., Ph.D., and Valerie Hervieu, M.D., Ph.D., of the University of Lyon, France; and Mitchell J. Frederick, Ph.D., of the University of Texas MD Anderson Cancer Center. The study was supported by funds from the National Institutes of Health and the AARC Carcinoid Foundation.

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Kidney care: A minimally invasive approach

UC Irvine innovative technique offers alternative to surgery.

By Camila Hernandez, UC Irvine

David and Ricki Pearl were meant to be together. They met as children and David proudly remembers it was love at first sight. Circumstances in life separated them for more than 30 years, but eventually they found each other again. Then, at age 70, David found out he had a growth in his kidney.

The specialist who discovered the growth told the Pearls he was certain it was cancerous, and David would need surgery right away. A biopsy would be too complicated, he said, because of the risk of seeding. Seeding is the spread of malignant cancer cells throughout the body.

The Pearls asked for a second opinion and were referred to Dr. Jaime Landman, chair of the Department of Urology at UC Irvine Health. Landman is a pioneer of a revolutionary minimally invasive ultrasound-guided technique that allows urologists to safely perform kidney biopsies with almost no risk of seeding.

Landman developed this innovative technique in collaboration with industry leaders and a team of UC Irvine Health urologists, anesthesiologists, nurses and medical students. After thorough testing in the lab, the team began performing ultrasound-guided kidney biopsies on patients, with excellent results.

The biopsy revealed that David Pearl’s tumor was not cancerous. Like David, many of the patients who undergo these biopsies turn out to have benign tumors and do not need surgery to remove the kidney. Nationally, up to 30 percent of kidney surgeries performed are unnecessary because tumors are later revealed to be benign.

“At UC Irvine Health, we are truly changing the way we diagnose and treat kidney cancer. No other medical center in Orange County is doing this,” Landman said. “I’m surprised we’re not doing this all over the world.”

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Healthy elders may hold key to fighting cancer

‘Wellderly’ may have unknowingly fought, beaten cancer; immune systems may hint at how.

The immune systems of healthy elders — the 'wellderly' — may be a protective factor against cancer. (Credit: iStock)

By Kate Rix, UC Newsroom

Could the immune systems of healthy seniors hold clues for beating the most aggressive form of breast cancer?

New evidence from the Scripps Research Institute suggests that some seniors may have successfully fought cancer without ever knowing it, developing antibodies that may hold promising avenues for new therapies.

Scripps researchers have begun mining the DNA in blood samples from the so-called “wellderly” — healthy adults age 80-plus — for the secrets to their long lives.

In the process, they’ve homed in on antibodies that bond with a type of cancer cell for which there is no targeted therapy.

“I thought that the human immune system is really our best defense against cancer,” says Brunie Felding, an investigator at Scripps. “The wellderly have had a healthy long life. My question was: Do these people have antibodies we should look into?”

Battles fought and won

With blood samples that included the combined white blood cells of cancer-free seniors, Felding found what may amount to the footprints, or memories, of past victories against cancer.

Exposed to an “immune library” generated from the wellderly blood samples, a particular protein in aggressive “triple negative” breast cancer cells was recognized by an antibody from the wellderly and sparked particular interest.

The cancer cell protein is part of a signaling pathway. “This could be a driving pathway in this aggressive cancer, an indicator of where to look for therapeutic targets,” says Felding.

The project was funded with two grants from the California Breast Cancer Research Program, which is managed by the UC Office of the President and supported in part by taxpayer donations on the state tax return.

The broader wellderly study, from which Felding obtained the blood sample, is ongoing at Scripps Research and led by professor Eric Topol.

Lingering antibody memory

Felding’s idea was novel: Healthy older women may have successfully fought breast cancer at some point and never known it. When the human body encounters a pathogen, it makes antibodies to neutralize it. Even when the pathogen is gone, the specially adapted antibodies remain in the immune memory, in case the pathogen reappears. A similar principle could control cancer development.

“If there were aberrant cells at some point in a person’s body, but a noticeable cancer never developed, the immune system likely coped with those stray cells, and the antibody memory would still be there years later,” Felding says.

In this study, researchers were specifically looking for how the body copes with what is called triple negative breast cancer. While many breast cancer tumors can be treated with anti-estrogen therapies, there is no targeted treatment for triple negative tumors.

“Finding an effective therapy for these types of breast cancers is one of our main goals in cancer research,” says Felding.

The cancer cells she exposed to the wellderly immune library were from a very aggressive triple negative breast cancer of a woman named Elizabeth, one of Felding’s friends, who died from the disease.

Looking at the genome of Elizabeth’s cancer, Felding and her group saw that the protein Apolipoprotein E, or ApoE, was more than 100-fold enriched during the progression of Elizabeth’s breast cancer.

They also found that this protein was recognized by some of the wellderly antibodies. This could mean two things: The antibodies that recognize ApoE may have certain disease-blocking properties and could hold promise for a targeted therapy. Or, ApoE might be a flashing signpost pointing researchers down a pathway to be analyzed as a possible disease driver.

“Overall, the concept of exploring the immune system is very promising,” Felding said. “The fact that the wellderly blood donors are in their 80s means that their immune memories are very rich.”

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Income inequality affects who get an underutilized test for breast cancer

UCLA-led study shows that economic factors may influence adoption of new technologies.

The study, led by UCLA’s Ninez Ponce, found that communities with greater gaps between high-income individuals and low-income individuals also had larger gaps in testing. (Photo by Shweta Saraswat, UCLA)

By Venetia Lai, UCLA

Wealthier women who live in communities with the greatest income divide between rich and poor had better access to a new genetic test that can determine the most effective form of treatment for early-stage breast cancer, according to a new study (link is password-protected) by the UCLA Center for Health Policy Research, Harvard Medical School’s Brigham and Women’s Hospital and Aetna. The study, published in the April issue of the journal Health Affairs, also indicated that only a small minority of women with breast cancer received the test at all.

“Our study shows that even among women who have insurance, where they live and how income is distributed in their community were closely linked to their chance of getting access to an effective innovation in the early years of its diffusion,” said Ninez Ponce, associate director of the UCLA Center for Health Policy Research and lead author of the study.

The Gene Expression Profiling test is an early example of a “precision medicine” genomic test that estimates a patient’s risk of having a recurrence of a disease. According to current medical evidence, a woman with early-stage, estrogen-receptor–positive, lymph-node–negative breast cancer with a low-risk GEP test score may not benefit from adding chemotherapy to her treatment plan, while a woman with a high-risk score would benefit and should consider including chemotherapy in her treatment. More than 100,000 women are diagnosed with this type of breast cancer every year.

The study is based on a survey of 1,847 women between the ages of 35 of 64 who were insured through an Aetna health plan and were newly diagnosed with breast cancer in 2006 and 2007. Of those, 235 (12.7 percent) had the GEP test.

The study found that the greater the gap between high-income individuals and low-income individuals within a community, the larger the gap in testing. In communities where there was greater equality in income — whether poorer or wealthier — the adoption and use of the tests was slower than in communities with unequal income levels.

“Income inequality is at an all-time high right now,” said Dr. Jennifer Haas, a co-author of the study and associate professor at Harvard Medical School’s Brigham and Women’s Hospital. “That it should have a bearing on who gets an innovative test and who doesn’t could lead to more social disparities in cancer care.”

The authors point to the need for more research to address the socioeconomic and other barriers that may prevent women from accessing GEP and other medical innovations.

The TRANSPERS Center for Translational and Policy Research on Personalized Medicine, the National Institutes of Health, Harvard Catalyst, the Harvard Clinical and Translational Science Center, and the National Research Service Award Primary Care Research Fellowship and Aetna supported this study.

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Dual therapy’s one-two punch knocks out drug-resistant lung cancer

Unusual chance to study patient’s residual tumor leads to new finding.

PET-CT imaging from a patient with EGFR-mutant lung cancer before (top) and after (bottom) treatment with the targeted drug erlotinib (Tarceva). By studying the residual tumor seen in the lower image, a UCSF team determined why the patient developed erlotinib resistance, and devised a strategy to overcome it. (Image courtesy of Collin Blakely)

By Pete Farley, UC San Francisco

Capitalizing on a rare opportunity to thoroughly analyze a tumor from a lung cancer patient who had developed resistance to targeted drug treatment, UC San Francisco scientists identified a biological escape hatch that explains the resistance, and developed a strategy in mice for shutting it down.

In experiments that combined the drug the patient had taken with a second compound that blocks off this newly discovered resistance pathway, the researchers were able to durably wipe out cancer cells in mice implanted with cells from the drug-resistant tumor.

“Even in cancers that are responding to targeted therapy by conventional criteria, resistance is already developing,” said the senior author of the new study, Trever Bivona, M.D., Ph.D., assistant professor of medicine and member of the UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC). “In this work we have begun to crack open the question of why residual disease persists after targeted therapy.”

Between 10 and 35 percent of non-small cell lung cancer (NSCLC) patients carry mutations in a gene that codes for a cell-surface protein called the epidermal growth factor receptor, or EGFR. As its name suggests, under normal circumstances, when a growth factor protein locks onto the EGFR, the receptor sends signals that prompt cells to divide and proliferate. But the EGFR mutations seen in NSCLC cause the receptor to be stuck in an “on” position, leading to rampant cell proliferation.

Over the past decade, medications such as erlotinib (trade name Tarceva), which precisely targets the EGFR and tamps down its activity, have advanced the treatment of EFGR-mutant NSCLC beyond chemotherapy, but significant challenges remain. As many as 30 percent of patients exhibit so-called primary resistance to EGFR inhibitors, in which the drugs have no detectable effect. And among patients who do respond, almost all have an incomplete response leading to acquired resistance, in which drug-resistant cells that survive treatment form residual, often lethal, tumors.

Understanding the biological basis of acquired resistance has proved difficult, partly because patients with late-stage lung cancer rarely undergo surgery, leaving scientists with few drug-resistant tumors to use in research. But as described in the online edition of Cell Reports today (April 2), a team of UCSF researchers recently had unusual access to a surgically resected tumor from an EGFR-mutant lung cancer patient who had experienced a substantial, but incomplete, response to erlotinib.

Led by first authors Collin Blakely, M.D., Ph.D., a clinical instructor at UCSF, and Evangelos Pazarentzos, Ph.D., a postdoctoral fellow, the research group analyzed cells from this tumor using next-generation genome sequencing in an effort to understand how the cells sidestepped erlotinib treatment. They found that the tumor cells retained the EGFR mutation targeted by erlotinib and had not acquired additional cancer-driving mutations, or any other mutations known to confer drug resistance. These results suggested that the cells were still potentially susceptible to erlotinib, but had enlisted some additional mechanism to survive treatment.

That mechanism was revealed when cells from the tumor were implanted in mice that were then treated with erlotinib. The drug effectively inhibited EGFR activity, but the researchers also observed a rapid, 10-fold increase in the activity of a pathway known as NF-kappa-B, and they discovered that this increase is mediated by a previously unknown biochemical complex formed within the tumor cells. Though primarily associated with the immune system, a growing body of work has tied the NF-kappa-B pathway to various forms of cancer.

An experimental drug known as PBS-1086 directly targets the NF-kappa-B pathway, and when the researchers coupled this drug with erlotinib, the implanted tumors shrank significantly, suggesting that combining a compound like PBS-1086 with erlotinib at the outset of therapy may help to prevent acquired drug resistance in EGFR-mutant NSCLC.

Combined drug regimens designed to overcome drug resistance at the outset of therapy are now the norm in treating certain forms of melanoma, said Bivona, and he believes PBS-1086 “has a shot” to play a similar role in NSCLC.

“The NF-kappa-B pathway is engaged by cells in response to EGFR inhibitors as a way to survive treatment,” Bivona said. “Excitingly, if we block that pathway with a novel drug while simultaneously administering the EGFR inhibitor, we see tumors shrink. In lung cancer patients treated with these drugs, and that’s a substantial number of patients, this could be a very powerful companion therapy to minimize or eliminate residual disease.”

Other HDFCCC researchers taking part in the research included Sourav Bandyopadhyay, Ph.D., assistant professor of bioengineering and therapeutic sciences, and Nevan J. Krogan, Ph.D., professor of cellular and molecular pharmacology.

The work was funded by the Bonnie J. Addario Lung Cancer Foundation; the National Institutes of Health; the Howard Hughes Medical Institute; the Doris Duke Charitable Foundation; the American Lung Association; the Sidney Kimmel Foundation for Cancer Research; the Searle Scholars Program; the California Institute for Quantitative Biosciences; and the Li Ka-shing Foundation.

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