 investigators could warrant reconsideration of current screening guidelines to include a poorly recognized cause of Lynch syndrome, the most common cause of hereditary colorectal and endometrial cancers. Their study, 

JNCCN—Journal of the National Comprehensive Cancer Network,

 concluded that the guidelines leave a significant number of patients undiagnosed

“When patients with Lynch syndrome—whose first cancers generally appear at an early age—aren’t diagnosed promptly, they don’t get appropriate follow-up or surveillance,” said 

director of Translational Genomics in the Department of Biomedical Sciences at Cedars-Sinai and lead author of the study. “They can go on to have multiple different cancers before they are finally diagnosed. If we could identify them when they have their first cancer, we could prevent additional cancers—or at least detect them earlier.”

Many colorectal and endometrial cancers have something called mismatch repair deficiency. This means that the tumor formed because of mistakes that occurred when DNA was copied during cell division.

In most cases of Lynch syndrome, this mismatch repair deficiency is caused by an inherited mutation in a DNA mismatch repair gene. But mismatch repair deficiency can also be caused by something called methylation. This is a change to a gene called MLH1.

“Methylation isn’t hard-wired into the gene the way a mutation is,” said Hitchins. “It’s added on, like debris clogging an engine. The engine itself is not defective, but it doesn’t work properly because it’s been clogged.”

 methylation is present in as many as 75% of tumors with mismatch repair deficiency, Hitchins said. It is usually present only in the tumor, meaning the defect is not inherited and the patient does not have Lynch syndrome.

“However, our study found that in a small fraction of patients, the methylation 

 present in normal tissues. It isn’t confined to the tumor. This predisposes cells to cancer development,” Hitchins said. “Because methylation is usually only present in the tumor, these patients have been automatically identified as non-Lynch patients, and never given the blood testing that would diagnose them with Lynch syndrome.”

To help determine how often this takes place, investigators reviewed data from two large retrospective population-based studies, and tested blood DNA from all mismatch repair deficient colorectal cancer patients who participated. Among patients age 55 and younger who had methylation in their tumors, 25%-75% also had methylation in their blood, meaning they had Lynch syndrome but had not been diagnosed.

 Hitchins and fellow investigators tested the blood of patients with endometrial cancer from the same patient populations. They found that approximately 30% of endometrial cancer patients had methylation in their tumors. And among those under age 50, 15%-20% also had methylation in their blood, indicating Lynch syndrome, Hitchins said.

“Taken together, these studies suggest this population of patients would benefit from a change in screening guidelines,” said 

, director of Cedars-Sinai Cancer and the PHASE ONE Distinguished Chair. “Appropriate screening can provide the opportunity for potentially lifesaving surveillance and early detection and treatment of subsequent cancers.”

For now, Hitchins recommends that colorectal cancer patients under age 56 and endometrial cancer patients under age 50 ask their healthcare providers about additional screening for themselves—and their parents, siblings and adult children. She also suggested that primary care providers and oncologists reach out to young patients from the past five years whose endometrial or colorectal tumors tested positive for MLH1 methylation.

“We’ve been finding young patients with endometrial or colorectal cancer who are told they don’t have Lynch syndrome, then go on to develop a colon or other cancer that might have been prevented, or at least detected earlier,” Hitchins said. “Those patients are walking around oblivious to their risk, and should be made aware of that fact and given the option of having a test.”

Funding: This study was funded by the National Cancer Institute of the National Institutes of Health R01 grant numbers CA218342, CA67941, and CA16058; a Cedars-Sinai Medical Center Precision Health Initiative Award; Spanish Ministry of Science grants SAF2015-68016-R, and PID2019-111254RB-I00; and travel fellowship number MINECO, EEBB-I-16-11581 from the Spanish Ministry of Economy, Industry and Competitiveness, and number RD12/0036/0031 from the RTICC network.

Articles

New research from Cedars-Sinai Cancer investigators could warrant reconsideration of current screening guidelines to include a poorly recognized cause of Lynch syndrome, the most common cause of hereditary colorectal and endometrial cancers. 

Missing a Rare Cause of Hereditary Cancer

As men age, some of their cells lose the very thing that makes them biological males—the Y chromosome—and this loss hampers the body’s ability to fight cancer, according to new research from 

The study, published today in the leading scientific journal 

 found that loss of the Y chromosome helps cancer cells evade the body’s immune system. This common impact of the aging process in men results in aggressive bladder cancer, but somehow also renders the disease more vulnerable—and responsive—to a standard treatment called immune checkpoint inhibitors.

Based on their research, investigators are developing a test for loss of the Y chromosome in tumors with the goal of helping clinicians tailor immune checkpoint inhibitor treatment for male patients with bladder cancer.

“This study for the first time makes a connection that has never been made before between loss of the Y chromosome and the immune system’s response to cancer,” said 

, director of Cedars-Sinai Cancer, the PHASE ONE Distinguished Chair and corresponding author of the publication, who initiated the research. “We discovered that loss of the Y chromosome allows bladder cancer cells to elude the immune system and grow very aggressively.”

Lead collaborators on the study also included Johanna Schafer, a postdoctoral fellow, and Zihai Li, MD, PhD, medical oncologist and immunologist, both at The Ohio State University Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute.

In humans, each cell normally has one pair of sex chromosomes; men have one X and one Y chromosome, while women have two X chromosomes. In men, loss of the Y chromosome has been observed in several cancer types, including 10%-40% of bladder cancers. Loss of the Y chromosome also has been associated with heart disease and Alzheimer’s disease.

The Y chromosome contains the blueprints for certain genes. Based on the way these genes are expressed in normal cells in the bladder lining, investigators developed a scoring system to measure loss of the Y chromosome in cancers.

The investigators then reviewed data on two groups of men. One group had muscle invasive bladder cancer and had their bladders removed, but were not treated with an immune checkpoint inhibitor. The other group participated in a clinical trial and were treated with an immune checkpoint inhibitor. They found that patients with loss of the Y chromosome had poorer prognosis in the first group and much better overall survival rates in the latter.

To determine why this happens, investigators next compared growth rates of bladder cancer cells from laboratory mice.

The investigators grew cancer cells in a dish where the cells were not exposed to immune cells. The researchers also grew the diseased cells in mice that were missing a type of immune cell called T-cells. In both cases, tumors with and without the Y chromosome grew at the same rate.

In mice with intact immune systems, tumors lacking the Y chromosome grew at a much faster rate than did tumors with the intact Y chromosome.

“The fact that we only see a difference in growth rate when the immune system is in play is the key to the ‘loss-of-Y’ effect in bladder cancer,” Theodorescu said. “These results imply that when cells lose the Y chromosome, they exhaust T-cells. And without T-cells to fight the cancer, the tumor grows aggressively.”

Based on their results derived from human patients and laboratory mice, Theodorescu and his team also concluded that tumors missing the Y chromosome, while more aggressive, were also more vulnerable and responsive to immune checkpoint inhibitors. This therapy, one of the two mainstay bladder cancer treatments available to patients today, reverses T-cell exhaustion and allows the body’s immune system to fight the cancer.

"Fortunately, this aggressive cancer has an Achilles’ heel, in that it is more sensitive than cancers with an intact Y chromosome to immune 

, associate professor at Cedars-Sinai Cancer and co-first author of the study with Schafer and Xingyu Chen, a research bioinformatician at Cedars-Sinai.

Preliminary data not yet published shows that loss of the Y chromosome also renders prostate cancers more aggressive, Theodorescu said.

“Our investigators postulate that loss of the Y chromosome is an adaptive strategy that tumor cells have developed to evade the immune system and survive in multiple organs,” said 

, executive vice president of Academic Affairs and dean of the Medical Faculty at Cedars-Sinai. “This exciting advance adds to our basic understanding of cancer biology and could have far-reaching implications for cancer treatment going forward.”

Further work is needed to help investigators understand the genetic connection between loss of the Y chromosome and T-cell exhaustion.

“If we could understand those mechanics, we could prevent T-cell exhaustion,” Theodorescu said. “T-cell exhaustion can be partially reversed with checkpoint inhibitors, but if we could stop it from happening in the first place, there is much potential to improve outcomes for patients.”

While women do not have a Y chromosome, Theodorescu said these findings could have implications for them as well. The Y chromosome contains a set of related genes, called paralogue genes, on the X chromosome, and these might play a role in both women and in men. Additional research is needed to determine what that role might be.

“Awareness of the significance of Y chromosome loss will stimulate discussions about the importance of considering sex as a variable in all scientific research in human biology,” Theodorescu said. “The fundamental new knowledge we provide here may explain why certain cancers are worse in either men or women, and how best to treat them. It also illustrates that the Y chromosome does more than determine human biologic sex.”

Funding: This work was supported in part by National Institutes of Health grant numbers P01CA278732, R01CA143971, R01CA262069, R01CA262388 and R01AI077283; an Ohio State University Comprehensive Cancer Center Tumor Immunology T32 post-doctoral fellowship award, and the Immune Monitoring and Discovery Platform and the Pelotonia Institute for Immuno-Oncology at OSU Comprehensive Cancer Center.

Cedars-Sinai Cancer investigators elucidate how this process allows bladder tumors to evade the immune system but also makes them vulnerable to a common treatment.


Loss of Y Chromosome in Men Enables Cancer to Grow

Physicians at Cedars-Sinai Cancer are using a unique chemotherapy delivery system that offers hope to colorectal cancer patients whose disease has spread and who now have inoperable liver tumors. 

Cedars-Sinai is one of the few centers in the area to offer the therapy, called hepatic artery infusion (HAI) pump chemotherapy.

“Many of these patients are not candidates for curative surgery and we now have a meaningful option for treating them,” said 

, chair of the Department of Surgery at Cedars-Sinai and a specialist in the care of patients with complex hepato-pancreato-biliary disorders. “This therapy has been shown to extend both life and quality of life.”

Colorectal cancer is the fourth-leading cause of cancer-related death in the U.S. In as many as 25% of patients diagnosed with the disease, the cancer spreads to the liver, where it can be difficult to treat. However, more than half of patients receiving hepatic artery infusion pump therapy go on to receive curative surgery, studies have shown.

, director of the Gastrointestinal Tumor Program at 

 and associate professor of Surgery at Cedars-Sinai, sat down with the 

We surgically place the pump underneath the skin, outside of the abdominal cavity, and it is attached to tubing that enters the abdominal cavity and goes into the gastroduodenal artery. That artery feeds into the hepatic artery, which supplies blood to the liver. During surgery, we block blood flow from the gastroduodenal artery from going into portions of the small intestine so that the therapy flows only to the liver.

The pump has a soft center, allowing its internal reservoir to be filled through the skin via a syringe. After surgery, the patient comes in every two weeks and we refill the pump, which then allows the chemotherapy drug to flow directly into the liver via the arterial supply.

Which patients are likely to benefit from hepatic artery infusion pump therapy?

This therapy is designed for patients, based on the distribution of the metastatic disease (where are the tumors and how many), for whom curative surgery is not an option at the time of diagnosis. The best we had been able to offer these patients was lifelong chemotherapy that had potential systemic toxicities, and that never quite reduced their tumor size to the point that we could surgically remove it. This therapy offers an additional option for liver-directed therapy that can potentially make patients candidates for surgery by specifically targeting the liver disease.

What are the advantages of the hepatic artery infusion pump over traditional chemotherapy delivery?

A majority of these tumors derive their blood supply from the hepatic arterial system, and delivering chemotherapy to the tumors through the hepatic arterial system allows us to give higher doses of specific chemotherapeutic agents without exposing the patient to their systemic toxicities. Data shows that up to 60% of appropriately selected patients receiving hepatic artery infusion pump chemotherapy were then able to receive curative surgery. Patients can often continue receiving systemic chemotherapy in combination with hepatic artery infusion pump chemotherapy.

Are hepatic artery infusion pumps used to treat other types of liver cancer?

Some patients with cholangiocarcinoma are currently treated with HAI pumps, but this is not yet standard of care. Colon cancer is the second most common cancer, and colon cancer that has metastasized to the liver affects a significant number of patients. And we have seen good outcomes with those patients. Other types of cancers that metastasize to the liver are significantly more challenging to treat, and thus far, we don't think this therapy will benefit those patients.

Hepatic artery infusion pumps have actually been around for about 25 to 30 years, but until quite recently only a few medical centers were using them. But more and more centers are realizing that this therapy can truly benefit patients, and it is becoming more widely available.

Physicians at Cedars-Sinai Cancer are using a unique chemotherapy delivery system that offers hope to colorectal cancer patients whose disease has spread and who now have inoperable liver tumors.

Targeted Chemotherapy Helps Cure Some Inoperable Tumors

Vitamin D deficiency could be the reason African American men experience more aggressive prostate cancer at a younger age compared with European American men, new research from 

 suggests. The multi-institutional study, published in 

 a journal of the American Association for Cancer Research (AACR), could pave the way for revised nutritional guidelines.

While previous research has investigated vitamin D in the context of health disparities, this is the first study to look at its functions in a genome-wide manner in African American versus European American men.

“African American men are more likely than European American men to develop prostate cancer, and are twice as likely to die from the disease,” said 

, research scientist at Cedars-Sinai Cancer and senior author of the study. "Large-scale studies have shown that differences in access to healthcare do not fully account for this health disparity, and our study identifies biological factors that might explain it." 

Vitamin D helps the body absorb calcium, which is essential for bone health, but it also helps stimulate the maturation of cells, Campbell said. Unlike normal cells, cancer cells do not mature and die. They continue to divide, creating more and more abnormal cells.

“Without sufficient levels of vitamin D to cause them to mature, the cells in a tumor continue to multiply out of control,” Campbell said.

Campbell and fellow investigators found that the vitamin D receptor, a protein that helps the body use vitamin D, appears to have adapted differently in people of African ancestry.

“The forebears of African American and European American men adapted to the climates where they originated,” Campbell said. “African men retain higher melanin levels in the skin to protect against the strong sun—which also helps the body produce vitamin D. Because of this, their descendants in the U.S., which receives fewer hours per year of bright sunshine than African countries do, are often vitamin D deficient.”

When investigators examined prostate cancer cells from patients of African and European descent, developed in the lab of Clayton Yates, PhD, at Johns Hopkins School of Medicine, they noted differences between how these groups of cells reacted to exposure to vitamin D.

“Their response to vitamin D was very, very different, including which genes the vitamin D receptor was controlling and the magnitude of that control,” Campbell said. “In African American men, this differing response made them more vulnerable to prostate cancer.”

Campbell noted that further research along these lines could lead to a revision of nutritional guidelines for vitamin D intake—for both bone and prostate health—based on genetic ancestry. Further work, he said, is needed to determine the level of vitamin D that would be most beneficial for each group, and to examine how the vitamin D receptor works with other proteins associated with prostate cancer.

“Cedars-Sinai Cancer delivers care to one of the most diverse populations in the US, and this study is an example of the many initiatives underway to unlock the root causes of health disparities,” said 

, director of Cedars-Sinai Cancer and the PHASE ONE Distinguished Chair. “It also shows how multi-institutional collaboration can maximize the potential of our work and why we place so much importance on our Community Outreach and Engagement (COE) team to engage diverse populations in cancer research.”

In addition to Yates, key partners in the study included Solomon Rotimi, PhD, of Covenant University in Nigeria; Adam Murphy, MD, of Northwestern Medicine in Chicago; Melissa Davis, PhD, and Rick Kittles, PhD, of Morehouse School of Medicine in Atlanta; and Chanita Hughes-Halbert, PhD, of the University of Southern California.

Campbell and colleagues plan further investigation of a group of microRNAs—small molecules that help regulate gene expression—in regions of the genome regulated by the vitamin D receptor. They found an association between these microRNAs and prostate cancer that could eventually be used to develop blood tests that offer a more complete picture of prostate health. The team also plans to examine vitamin D and its relationship to health disparities in other hormone-dependent cancers, such as breast cancer.

Funding: This study was supported by Prostate program of the Department of Defense Congressionally Directed Medical Research Programs grant numbers W81XWH-20-1-0373 and W81XWH-21-1-0850; National Institute on Minority Health and Health Disparities of the National Institutes of Health grant numbers U54-MD007585-26 and U54MD010706; National Cancer Institute of the National Institutes of Health grant number U54 CA118623; Department of Defense grants PC170315P1 and W81XWH-18-1-0589; and National Institutes of Health Cancer Center Support grant number P30CA016058.

Vitamin D deficiency could be the reason African American men experience more aggressive prostate cancer at a younger age compared with European American men. 

Study: Vitamin D May Play a Role in Prostate Cancer Disparities

 are collaborating on a streamlined clinical trial design in a study called Pragmatica-Lung. This randomized Phase III trial funded by the National Cancer Institute (NCI), part of the National Institutes of Health, will test a therapy for advanced non-small cell lung cancer in a real-world patient population, with a focus on just one major question: Does this therapy help patients live longer?

Although the answer is important, researchers everywhere are watching the trial for its practical design as a clinical study open to a broad patient population with non-small cell lung cancer. Most new drug clinical trials have strict rules about participants’ diagnoses, medical conditions, functional status and other factors.

“The design of this clinical trial could change the paradigm for how some drugs undergo approval, ultimately increasing the number of participating medical centers and the number of participants who are able to enroll,” said 

, associate director for Clinical Research in Cedars-Sinai Cancer, director of Medical Oncology in the 

 and principal investigator for Pragmatica-Lung. “This may open the doors to patients who might not otherwise be offered clinical trials.”

NCI collaborators for the Pragmatica-Lung Study include the SWOG Cancer Research Network, which designed and is leading the trial in collaboration with the Alliance for Clinical Trials in Oncology, and the pharmaceutical companies Merck (known as MSD outside the U.S. and Canada) and Eli Lilly and Company, each of which is providing one of the study drugs and additional trial funding. The study will be conducted with participation of the four U.S. NCI National Clinical Trials Network (NCTN) groups that focus on cancer in adults. The trial opened nationwide in March. Interested patients can learn more at 

The therapy being tested—a combination of the medications ramucirumab and pembrolizumab, each previously approved by the Food and Drug Administration—was most recently examined in a SWOG randomized 

 funded by the NCI that was led by Reckamp. The study, in patients whose cancer had returned after chemotherapy and immunotherapy, concluded that the combination therapy significantly extended the lives of patients with one of the most common forms of lung cancer.

The results of that trial, presented in June at the American Society of Clinical Oncology annual meeting, were promising enough for a Phase III trial to follow. But creating and completing a Phase III trial can take years.

“We know that treatments for non-small cell lung cancer are evolving rapidly, so to wait many years to start a trial to confirm the results of this well-designed Phase II trial didn’t seem to make a lot of sense,” Reckamp said. “We have safe, FDA-approved drugs. We wanted to create a simple trial that would quickly tell us whether this combination improves patient survival over standard of care.”

There are three major factors that can cause a trial to lag, all of which Pragmatica-Lung aims to address:

Burdensome enrollment criteria that require patients to submit imaging, tissue samples and other labs in order to ensure only ideal participants are included

The requirement that research staff collect and report every side effect occurring in every patient, even if that side effect is not serious or unexpected

Evaluation of multiple outcomes, such as whether or not a patient’s tumor continues to progress, regardless of how that affects patient survival

But the combination of ramucirumab and pembrolizumab—two FDA-approved medications that research has shown can be safely combined—seemed a good candidate for a new trial design that trims data collection requirements to a minimum.

“The FDA and the Clinical Trials Advisory Board have recently been exploring the idea of more streamlined, more practical clinical trials, and this is a good opportunity to move this idea into practice,” Reckamp said.

Reckamp and a team of others involved with the Phase II study began discussions with the NCI and members of the NCTN.

“We presented the Phase II data in June, and by November we had the Pragmatica-Lung protocol reviewed by the NCI Central Institutional Review Board,” Reckamp said. “This is breakneck speed not generally seen in developing a new trial.”

“This pragmatic approach could really speed up clinical trials and decrease the cost of trials,” said James H. Doroshow, MD, director of NCI’s Division of Cancer Treatment and Diagnosis. “We can do more studies that provide more answers for patients more quickly.”

The team simplified the eligibility criteria, allowing most patients with non-small cell lung cancer that had recurred despite chemotherapy and immunotherapy to be enrolled. This means virtually any NCTN institution in the U.S. treating lung cancer could participate.

“It empowers investigators to treat as they would in the real world and allows a much broader population to go on the trial,” Reckamp said. “By opening this up and making it simpler, we hope to increase the diversity of our study sample, and we have a plan, in conjunction with SWOG and other groups, to reach out to underrepresented groups to further extend our reach.”

Once the trial is underway, investigators will collect data only on serious and unexpected side effects, and the trial will only look at overall survival rates.

“For patients with cancer, survival is the gold standard,” Reckamp said. “And if this simplified trial produces a reasonable outcome, other groups may start to follow this model.”

Reckamp said that this type of trial isn’t right for therapies where safety data hasn’t previously been collected, but that the FDA and the NCI are highly invested in making these types of trials work where appropriate.

“Pragmatica-Lung should ease the burden on sites interested in conducting clinical research in non-small cell lung cancer while steadfastly improving outcomes for patients and ushering in new treatment paradigms,” said 

, director of Cedars-Sinai Cancer and the PHASE ONE Distinguished Chair. “And thanks to the streamlined trial design, whether the outcome is positive or negative, the findings will have an impact.”

Investigators from Cedars-Sinai Cancer are collaborating on a streamlined clinical trial design in a study called Pragmatica-Lung. 

Cedars-Sinai Cancer Collaborates on a New Type of Clinical Trial

In a large-scale nationwide study, investigators from 

 have confirmed that rates of pancreatic cancer are rising—and are rising faster among younger women, particularly Black women, than among men of the same age. Their work was published today in the peer-reviewed journal 

“We can tell that the rate of pancreatic cancer among women is rising rapidly, which calls attention to the need for further research in this area,” said 

, associate director of Pancreatic Biliary Research at Cedars-Sinai and senior author of the study. “There’s a need to understand these trends, and to make changes today so this doesn’t affect women disproportionately in the future.”

The pancreas, located just behind the stomach, secretes enzymes and hormones that help the body digest food and process sugars. Pancreatic cancer has the highest mortality rate of all major cancers, accounting for 3% of all cancer deaths in the U.S., and is more common among men than women.

In this study, investigators combed through data on patients diagnosed with pancreatic cancer between 2001 and 2018 from the National Program of Cancer Registries (NCPR) database, which represents approximately 64.5% of the U.S. population.

Investigators found that rates of pancreatic cancer increased among both women and men. Unexpectedly, rates among women under the age of 55 rose 2.4% higher than rates among men of the same age, while similar increased rates were observed among older men and women. Furthermore, rates among young Black women rose 2.23% higher than among young Black men.

“And while we’re reporting improving survival in pancreatic cancer each year, that improvement is largely among men,” Gaddam said. “The mortality rate among women is not improving.”

One possible explanation put forward by the investigators pertains to the type and location of tumors. Rates of pancreatic head adenocarcinoma, an especially aggressive and deadly type of tumor situated at the head of the pancreas, appear to be increasing, the investigators found.

While Gaddam said it is important for future studies to examine the cause of these trends, he stressed that at this point the increase is small and his findings shouldn’t be cause for alarm.

"The data shows us a small increase in risk of pancreatic cancer,” he said. “And that awareness might refocus people on the need to stop 

smoking, reduce alcohol use, eat a healthy diet, exercise regularly and manage their weight. These lifestyle changes all help decrease the risk of pancreatic cancer.”

People with chronic abdominal pain are often concerned that they have pancreatic cancer, but Gaddam said that is usually a sign of another condition. However, people experiencing unexplained weight loss or jaundice—a yellowing of the skin and the whites of the eyes—should seek medical attention as these are potential signs of pancreatic cancer or other serious medical issues.

Looking ahead, Gaddam’s research will focus on determining the causes of these trends, including examining potential differences between pancreatic tumors in women and in men.

“This continuing work will help us to evaluate the effectiveness of new healthcare interventions, with the goal of identifying and addressing disparities in patient outcomes and access to effective treatment,” said 

, director of Cedars-Sinai Cancer and the PHASE ONE Distinguished Chair. “This is an ongoing focus throughout Cedars-Sinai Cancer as we serve our diverse population and can also inform public health policies to benefit patients everywhere.”

How to Manage Your Pancreatic Cancer Risk

Cedars-Sinai investigators verify that rates are trending up for both sexes; younger women and Black women see steepest increase.


Study Confirms Pancreatic Cancer Rates Rising Faster in Women Than Men

 have identified genetic signatures that could predict whether tumors in patients with bladder and other cancers will respond to immunotherapy. Their results, published today in the peer-reviewed 

Journal of the National Cancer Institute,

 could one day help guide clinicians to the most effective treatments for cancer patients.

“Our work indicates that these genetic signatures may prove to be tremendously valuable in predicting immunotherapy response in patients with bladder cancer, but also other tumor types,” said 

, director of Cedars-Sinai Cancer, the PHASE ONE Foundation Distinguished Chair and senior author of the study. “We will continue investigating these biomarkers with the goal of bringing them into clinical use and improving patient outcomes.”

During the past five years, anti-PD-1/PD-L1 therapy—a type of cancer immunotherapy that paves the way for the body’s immune system to attack tumor cells—has proved effective against many cancer types, according to 

, a translational scientist, professor of Pathology and co-author of the study.

“It has proven very effective against melanoma and revolutionized lung cancer treatment,” Chan said. “Bladder cancer is considered one of the more responsive tumor types, but still has just a 25% durable response rate, so improvement is still needed.”

When a tumor causes a host immune reaction, immune cells usually are able to infiltrate the core of the tumor, and scientists call it a “hot” tumor. Some tumors, on the other hand, block immune cells from infiltrating and are known as “cold” tumors.

 by Theodorescu implicated a gene—called discoidin domain receptor tyrosine kinase 2 (DDR2)—in contributing to anti-PD-1 resistance in animal models in several tumor types. In a collaboration between cancer biologists and bioinformatics researchers, this new study further investigated the DDR gene family using human cancer data sets in various tumor types.

, a computational biologist with expertise in urologic oncology and first author of the study, analyzed data from The Cancer Genome Atlas program, a publicly available database with information on hundreds of cancer samples, to look at how expression of DDR2 and related gene DDR1 correlated with the host immune response to a tumor using bladder cancer as a model. He also looked at how genes regulated by DDR2 and DDR1 (i.e., gene signatures) correlated. He then looked at patient data from IMvigor 210, a clinical trial that evaluated immunotherapy response in bladder cancer, to see if these responses correlated with DDR2 and DDR1 expression or their related gene signatures.

The investigators came away with two key findings.

First, while the DDR1 and DDR2 genes are members of the same family, they have very different effects on tumors. Tumors with high expression of DDR1 tend to exhibit low expression of DDR2 and vice versa. And high DDR1 tumors are “cold,” while high DDR2 tumors are “hot.”

Investigators also identified four unique gene signatures modulated by DDR1 and DDR2 that were closely associated with tumor response to immunotherapy. They checked these genetic signatures in several additional sets of publicly available patient data across multiple cancer types.

“We found that these gene signatures were clearly associated with response to immunotherapy in bladder cancer and lung cancer tumors in multiple patient groups,” You said. “We also evaluated the signatures in publicly available data on melanoma, glioblastoma and blood cancers, with similar results.”

“The next step is to validate these signatures in a prospective clinical trial,” said Theodorescu. “This could yield new tools that allow clinicians to determine pre-treatment whether given patients will likely respond to anti-PD-1/PD-L1 therapy. They can then proceed with anti-PD-1/PD-L1 therapy for those patients who will derive the most benefit, and offer alternative therapies for patients not likely to respond, improving outcomes for all.”

Cedars-Sinai cancer researchers identify new biomarkers linked with patient response to immunotherapy for many types of cancers.

Genetics May Predict Bladder Cancer Immunotherapy Response

 and Johns Hopkins University have discovered a novel three-step treatment that disrupts the pancreatic tumor microenvironment in laboratory mice. 

The preclinical study, published in the peer-reviewed journal 

, focuses on a trio of drugs that prevented cancer metastasis; the spread of disease to other parts of the body. The preclinical study also is the first to identify synergistic effects of targeting both inside the cell and the tumor microenvironment outside of the cells.

“These three drugs, used in combination in a laboratory setting, prevented disease metastasis,” said 

Pancreatic Cancer Multidisciplinary Clinic

 and Precision Medicine Program at Cedars-Sinai Cancer and senior and corresponding author of the study. “By focusing on the difficult-to-treat tumor microenvironment, we were able to amplify an immune response while simultaneously attacking cancerous cells.”

The three-step combinatorial strategy combined an anti-PD-1 immunotherapy antibody and a protein known as FAKi with a novel pathway called CXCR4. This combination destroyed the tumor’s outer microenvironment, attacked the tumor itself, and bolstered the immune system of the laboratory mice.

“The combined therapy prevented disease metastasis and extended life,” said Osipov, also a medical oncologist and researcher in the Gastrointestinal Research Group at the Samuel Oschin Cancer Center. “This is an important step for a disease that is extremely challenging to treat and has very low survival rates.”

The tumor microenvironment in pancreatic ductal adenocarcinoma—the most common form of pancreatic cancer—has long been resistant to therapeutics, including immunotherapy.

Pancreas tumors tend to be aggressive and often become resistant to traditional treatments like chemotherapy. While immunotherapies have proven successful in many other forms of cancer—like melanoma and lung cancer—benefits have been limited in pancreatic cancer.

This difficulty to treat the disease has made pancreatic cancer one of the deadliest cancers, with a five-year survival rate of just 11%.

More than 62,000 Americans are expected to be diagnosed with pancreatic cancer in 2022. And, by the year 2030, 

 is expected to become the second-leading cause of cancer-related death in the United States.

“Our teams of investigators are exploring novel methods to target the tumor microenvironment with the hope of improving survival and treatment options for patients,” said 

, director of Cedars-Sinai Cancer and the PHASE ONE Foundation Distinguished Chair. “This innovative research study emphasizes how simultaneously targeting both intracellular and extracellular components of the microenvironment may improve an immunotherapy response.”

As a next step, Osipov and team plan to develop a clinical trial to further explore the treatment potential of the CXCR4 pathway.

Cedars-Sinai cancer study shows novel strategy disrupts the difficult-to-treat tumor microenvironment, preventing cancer from spreading.


Cedars-Sinai Cancer