Individual proteins coalesce to create an intricate network. When intact, that network protects certain cancers against cell death during their transformation into malignancies, new collaborative research from Weill Cornell Medicine and Memorial Sloan Kettering shows. The investigators also discovered that the loss of just one protein will cause the network’s collapse, as well as the death of the cancer cells that depend on it — a finding that may advance the development of targeted therapies for some patients.

The use of biochemical tools enabled the investigators to identify these protein networks, showing them where precisely to target their therapies to eliminate the related tumors.

“It’s a way to have precision medicine that’s based not on genetics, but rather on the properties of protein networks. If you disrupt the networks, the tumors die,” said co-senior author Dr. Monica L. Guzman, an associate professor of pharmacology in medicine at Weill Cornell Medicine, who collaborated with co-senior author Dr. Gabriela Chiosis, a member and a professor in the Tri-Institutional Program in Chemical Biology at the Sloan Kettering Institute.

Researchers have long known that individual proteins that belong to a family called the chaperome perform important functions in normal and cancer cells. In their study, published Oct. 5 in Nature, the investigators discovered that certain stresses in the cellular environment force these chaperomes to band together to form highly integrated protein networks known as epichaperomes. These networks allow cancers to avoid cell death during malignant transformation, supporting their growth into tumors.

“This Nature study provides the mechanistic basis for the development of epichaperome-targeted therapeutics,” Dr. Guzman said, “and demonstrates that evaluation of the epichaperome enables prospective identification of patients who may benefit from epichaperome-targeted therapeutics.”

To assess the prevalence of these complex protein networks in tumors, and to understand the mechanisms behind their formation, the investigators examined tissue samples from a large panel of pancreatic, gastric, lung and breast cancer cell lines, as well as lymphomas and leukemias. Of the samples they analyzed, researchers found 60 to 70 percent to contain medium-to-high levels of epichaperomes. Analyses of primary liquid tumors and solid tumors, including lymphomas, produced similar results, indicating that epichaperome-targeting therapies can be used across tumor types.

The researchers also identified the cancer-causing gene MYC — which is behind most aggressive types of cancer — to trigger the formation of epichaperomes. When activated in cancer, MYC causes a large production of proteins that work overtime to make cancer cells duplicate.

The ability to dismantle these complex protein networks may lead to new cancer treatments, the investigators said. The next steps for Drs. Guzman and Chiosis are to find out how they can exploit tumors’ addiction to epichaperome networks so they can be eliminated with therapy.

Foundational Infrastructure to Drive New Advances in Cancer Immunotherapy Launched With $2 Million Gift

Portion of Gift Dedicated to Establish Key Research Collaborations between Investigators at Weill Cornell Medicine and Cornell University

NEW YORK (October 25, 2016) –With the goal of advancing a powerful cancer treatment strategy that uses immune cells to fight the disease, benefactors Ellen and Gary Davis have generously made a $2 million gift to Weill Cornell Medicine to drive ongoing research in immunotherapy, the institution announced today.

This significant, foundational gift will launch the Ellen and Gary Davis Immune Monitoring Core, a critical research infrastructure that will serve as a repository for patient tumor samples, genomic sequencing and bioinformatics. The core will analyze and provide centralized, sensitive and quantitative patient data that investigators can use to advance their research into immunotherapy. The gift lays the cornerstone for further expansion in immunotherapy research and strengthens Weill Cornell Medicine's position as a leader in the development of powerful new weapons in the fight against cancer. A portion of the gift will fund research collaborations between investigators at Weill Cornell Medicine, Cornell University and Cornell Tech, strengthening the critical bridges between New York and Ithaca.

"We are extremely grateful to Ellen and Gary, whose strategic gift establishes an important foundation for immunotherapy research that is befitting of the treatment's promise," said Jessica M. Bibliowicz, chairman of the Weill Cornell Medicine Board of Overseers. "Ellen and Gary's generous support will augment our growing immunotherapy program, bolster our rich research communities at Weill Cornell Medicine and Cornell University, and bring us closer to eliminating cancer."

The Davises have a legacy of philanthropy at Cornell University, including generously endowing the Gary S. Davis Professorship of Government, the Gary and Ellen Davis Curator of Photography at the Herbert F. Johnson Museum of Art in Ithaca, and establishing a joint fellowship at the Meinig School of Biomedical Engineering and Weill Cornell Medicine to advance research into epilepsy.

"All of us at Cornell are profoundly grateful to the Davises for their immense generosity and vision, which will accelerate the pace of scientific discovery and ensure that more patients benefit from immunotherapy," said Hunter R. Rawlings III, interim president of Cornell University. "With this outstanding new gift, Ellen and Gary are strengthening the bonds between our faculty in Ithaca and New York City; their collaboration will inspire new investigative avenues that will truly make a difference."

"Immunotherapy represents one of the most exciting avenues of investigation for fighting cancer," said Weill Cornell Medicine overseer Ellen Davis and Cornell University trustee and alumnus Gary Davis. "We are proud to be able to make this important investment, empowering Weill Cornell Medicine and its unparalleled oncology program, led by Dr. Lewis Cantley, as well as the distinguished investigators at Cornell in Ithaca and engineers at Cornell Tech, to realize the promise of immunotherapy."

"Cancer is a devastating disease, and it is our responsibility to find new, more effective and more tolerable treatments that will allow patients to get back to their everyday lives," said Dr. Augustine MK Choi, interim dean of Weill Cornell Medicine and interim provost for medical affairs at Cornell University. "Ellen and Gary Davis' transformative gift helps us to do just that, providing valuable resources and fostering research collaborations so that we can perfect immunotherapy. We thank these champions of groundbreaking biomedical research for their incredible generosity."

Immunotherapy has become a promising new therapy for many types of cancers, hailed as the "fifth pillar" alongside surgery, radiation, chemotherapy and precision-targeted therapeutics. While the latter four attempt to remove or attack cancer cells directly, immunotherapy utilizes a patient's own immune system to strike the disease from within. Scientists have made important advances in this therapeutic area that have improved patients' lives and the outcomes of their diseases. However, most patients do not respond to immunotherapy alone, and it is not yet possible to predict who may need secondary, complementary treatments — or who may have developed treatment resistance. The Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine is committed to overcoming those obstacles.

"Immunotherapy is an emerging frontier in medicine that, by leveraging patients' own immune systems to confront cancer, has the potential to profoundly change the way we treat the disease," said Dr. Cantley, director of the Sandra and Edward Meyer Cancer Center and a professor of cancer biology in medicine at Weill Cornell Medicine. "Thanks to the Davises' generosity and steadfast dedication to improving health, we will now be able to advance our understanding of this powerful therapeutic avenue, ensuring that more patients benefit from immunotherapy."

The Davises first met Dr. Cantley in connection with a three-year team science grant, which they underwrote for The Melanoma Research Alliance to support his cancer research.

The Ellen and Gary Davis Immune Monitoring Core will be a valuable, shared resource for Weill Cornell Medicine's Meyer Cancer Center and Caryl and Israel Englander Institute for Precision Medicine. In order to drive new scientific breakthroughs and innovations that may enhance the potential of immunotherapy, the core will offer a robust technological infrastructure that will allow investigators to analyze, sequence and archive tumor samples, explore the tumor microenvironment, and conduct expression studies. Bioinformatics technology will empower scientists to examine the array of data from those studies and translate their findings into assays that can be used to measure the efficacy of immunotherapy for each patient. Insights gleaned from those tests will be used to inform ongoing treatment decisions, determine effective adjunct therapies, and predict patient response and resistance to therapy.

Underscoring the special synergy between Cornell University, Weill Cornell Medicine and Cornell Tech, the Davises have dedicated $400,000 of their gift to fund research collaborations between investigators in New York and Ithaca. The research support, offered through competitive grants, will enable investigators to drive new innovations in immunotherapy that will benefit patients in New York and beyond.

About Ellen and Gary Davis

A graduate of the Wharton School of the University of Pennsylvania, Ellen Davis is currently an active principal, investor and advisor for early-stage businesses. She previously worked for Merrill Lynch in its High Yield Department and was an Associate in Corporate Finance at Drexel Burnham Lambert. Committed to advancing medical research, Ms. Davis joined the Weill Cornell Medicine Board of Overseers in 2015 and serves on its Special Committee on Research, as well as its Membership and Nominating Committee. She is also a member of the Board of Directors of the Melanoma Research Alliance, the largest private funder of melanoma research, and is on the Advisory Board of the Roy Vagelos Program in Life Sciences and Management at the University of Pennsylvania. A leader in other nonprofit endeavors, Ms. Davis developed and launched a virtual JCC platform for Greenwich, Conn. and currently serves as the chairman of the Board of JCC/UJA Greenwich. Ms. Davis is a member of the Trustees' Council of Penn Women and served as a member of the Horace Mann School Board of Trustees from 2009-2015.

Gary Davis received a bachelor's degree from Cornell University in 1976 and a Master in Business Administration and Juris Doctor degree from Columbia University in 1980. He is currently CEO of DKR Capital Partners, an investment advisory firm engaged primarily in the hedge fund and private equity markets. Mr. Davis began his career in 1980 in private law practice with the New York law firm Paul, Weiss, Rifkind, Wharton & Garrison. He joined Drexel Burnham Lambert two years later, where he served in various managerial positions and, ultimately, as its president until 1990. Mr. Davis went on to co-found and lead AIG Trading Group as its president and CEO.

A Cornell trustee since 2012, Mr. Davis is a member of the board's Executive Committee and co-chair of the Development Committee, as well as a vice chair of the Investment Committee and member of the Finance Committee. He was the Cornell Class of 1976 president from 2011-16 and chaired two of his class's most recent reunion committees. Mr. Davis also chairs the Herbert F. Johnson Museum of Art Advisory Council, and is a member emeritus of the College of Arts and Sciences Advisory Council. He serves as co-chair of the Columbia University Law School Dean's Council, and is a member of the Stratton Mountain School Board of Trustees and co-chair of its Finance Committee, as well as of the Metropolitan Museum of Art Photography Department Visiting Committee. Mr. Davis previously served as a member and development chair of the Solomon Schechter Day School Board of Trustees.

Weill Cornell Medicine

Weill Cornell Medicine is committed to excellence in patient care, scientific discovery and the education of future physicians in New York City and around the world. The doctors and scientists of Weill Cornell Medicine—faculty from Weill Cornell Medical College, Weill Cornell Graduate School of Medical Sciences, and Weill Cornell Physician Organization—are engaged in world-class clinical care and cutting-edge research that connect patients to the latest treatment innovations and prevention strategies. Located in the heart of the Upper East Side's scientific corridor, Weill Cornell Medicine's powerful network of collaborators extends to its parent university Cornell University; to Qatar, where Weill Cornell Medicine-Qatar offers a Cornell University medical degree; and to programs in Tanzania, Haiti, Brazil, Austria and Turkey. Weill Cornell Medicine faculty provide comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center, NewYork-Presbyterian/Lower Manhattan Hospital and NewYork-Presbyterian/Queens. Weill Cornell Medicine is also affiliated with Houston Methodist. For more information, visit weill.cornell.edu.

Urothelial cancer evolves at the genetic level over time and through treatment. These microscopic images show the differences in the number of copies of the CDKN2A gene (magenta color) as the tumor evolves from the primary bladder urothelial cancer (Top) to spread to the lymph node after treatment (Bottom).

All images: Nature Genetics

Chemotherapy is indicated as the first line of treatment for advanced bladder cancer. New research by Weill Cornell Medicine and University of Trento scientists shows that while chemotherapy kills the most common type of bladder cancer, urothelial cancer, chemotherapy also shapes the genetic evolution of remaining urothelial cancer cell clones to become drug-resistant.

Treatments for urothelial cancer are limited. Within months of the initial treatment, usually with platinum-containing chemotherapy, most patients will become resistant to treatment. Although immunotherapy has shown recent promise, there is no consistent cure for this chemotherapy-resistant state of the disease.

In their study, published Oct. 17 in Nature Genetics, investigators from Weill Cornell Medicine and the University of Trento discovered that urothelial cancer cells mutate following treatment with chemotherapy, and that these mutations provide these tumor cells with an evolutionary advantage to survive chemotherapy. The findings lay the foundation for building a framework to understand the biological basis for chemotherapy-resistance in bladder cancer, which may lead to improved diagnostics and treatments for this lethal disease.

"We wanted to understand how chemotherapy changes urothelial cancer and to do so we had to apply the principles of evolution," said co-first author Dr. Bishoy M. Faltas, an instructor in medicine at Weill Cornell Medicine and an oncologist in the Genitourinary Oncology Program in the Division of Hematology and Medical Oncology at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center. "We found that chemotherapy acts as a selection pressure favoring the survival of the fittest urothelial cancer cell clones. By understanding how these urothelial cancer clones evolve at the genetic level over time and through different selective pressures such as treatment, we are hoping to translate our findings to strategies that reverse or prevent the emergence of chemotherapy resistance in bladder cancer patients."

The investigators collected and analyzed the DNA sequences of all coding genes (using a technique called whole-exome sequencing) in tumor samples at various stages of the disease from 32 patients with advanced urothelial cancer who consented to participate in the study at Weill Cornell Medicine and NewYork-Presbyterian. Of those, 28 had developed metastatic urothelial cancer at the time of enrollment or at a later point during the course of the study; two patients consented to undergo rapid autopsies, conducted within six hours after death, enabling the researchers to collect samples of tumors from different body sites that capture the natural history of the tumors' evolution.

Researchers at the Caryl and Israel Englander Institute for Precision Medicine at Weill Cornell Medicine sequenced the DNA extracted from patients' tumor samples obtained at different time points through the disease course. The bioinformatic analysis was conducted at the University of Trento in Italy by co-first author Dr. Davide Prandi, a postdoctoral fellow, and co-senior author Dr. Francesca Demichelis, the principal investigator at the Laboratory of Computational Oncology at the university's Centre for Integrative Biology. The computational biologists compared the genetic sequences of the primary untreated and the chemotherapy-treated tumor cells from the same patients side by side, noting where the genetic mutations were the same and where they differed.

The researchers found that the primary untreated and advanced chemotherapy-resistant tumors didn't share the majority of mutations. Rather, as the tumor spread, it branched out and developed new mutations that were different from those in the primary tumor, and it appeared to happen very early during the disease's development. This finding has important clinical implications for developing targeted therapies, according to Dr. Faltas, because clinical genomic testing, which is typically performed only on a single tumor site (usually the primary untreated tumor), does not capture the entire repertoire of genetic changes that occur after chemotherapy treatment.

The investigators also found that two molecular pathways — the integrin signaling and the L1-cell adhesion molecule signaling pathways — particularly accumulated higher levels of mutations after chemotherapy. They believe that these pathways are potential targets for preventing or reversing chemotherapy resistance in urothelial cancer. Finally, the researchers studied the mechanisms underlying the mutational changes they observed in chemotherapy-resistant urothelial cancer. They found that chemotherapy-treated urothelial cancers have more mutations caused by a family of proteins called APOBECs which mutate single-stranded DNA. Because chemotherapy drugs introduce breaks in double-stranded DNA, leaving single strands dangling, the investigators postulate that the APOBECs bind to these overhanging single strands of DNA in urothelial tumor cells, thus causing an increase in mutations in chemotherapy-treated tumors.

This study exemplifies the "team-science" approach to answering an important biological question with important clinical implications. This may ultimately translate to precision medicine strategies for bladder cancer patients.

"Precision cancer care does not know any borders or geographic restrictions," said co-senior author Dr. Mark Rubin, director of the Englander Institute for Precision Medicine and the Homer T. Hirst III Professor of Oncology in Pathology at Weill Cornell Medicine, and director of the precision medicine program at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center. "Our collaboration between cancer physicians and laboratory scientists in New York and computational scientists in northern Italy reminds us that our problems are similar and by working together — sharing data and observations — we can improve how we take care of patients in New York, Trento and beyond."

Researchers can now predict the odds of experimental drugs succeeding in clinical trials, thanks to a new data-driven approach developed by Weill Cornell Medicine scientists. The method detects toxic side effects that may disqualify drugs from human use, giving drug developers an early warning before initiating clinical trials, according to a new study published Sept. 15 in Cell Chemical Biology.

The approach upends conventional wisdom about the criteria on which to evaluate new drugs for their safety. Rather than exclusively examining molecular structure to determine viability, this new computational method combines a host of structural features and features related to how the drug binds to molecules in the body.

"We looked more broadly at drug molecule features that drug developers thought were unimportant in predicting drug safety in the past. Then we let the data speak for itself," said author Dr. Olivier Elemento, an associate professor of physiology and biophysics and of computational genomics in computational biomedicine, associate director of the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine, and head of the computational biology group at the Caryl and Israel Englander Institute for Precision Medicine.

The method, known as PrOCTOR, was inspired by an approach that baseball statisticians adopted to better predict which players would be successful offensively. Instead of relying on collective wisdom from baseball insiders, statisticians decided to use an objective numbers analysis to measure in-game productivity, a strategy known as "Moneyball."

Similarly, researchers developed a computational method that analyzes data from 48 different features of a drug — from molecular weight to details about its target — to determine whether it would be safe for clinical use. Using a form of artificial intelligence called machine learning, the investigators trained PrOCTOR on hundreds of U.S. Food and Drug Administration-approved drugs and drugs that failed clinical trials due to toxicity problems.

Kaitlyn Gayvert

Based upon this information, the investigators created "PrOCTOR scores" that could help distinguish drugs approved by the FDA from those that failed for toxicity. They tested PrOCTOR on hundreds of additional drugs approved in Europe and Japan and using side-effect data on approved drugs collected by the FDA. PrOCTOR was able to accurately recognize toxic side effects that were a consequence of a drug's chemical features and its target. Records revealing that many of these drugs had failed clinical trials supported PrOCTOR's accuracy.

"We were able to find several features that led to a very predictive model," Dr. Elemento said. "Hopefully this approach could be used to determine whether it's worth pursuing a drug prior to starting human trials."

He added that the method could also be utilized for post-approval surveillance of drugs that are currently approved by the FDA but may still be toxic. For example, PrOCTOR predicted that an FDA-approved diabetes drug was toxic, and upon further investigation, Dr. Elemento and his team discovered that it had been withdrawn from European markets.

But when it comes to toxicity, first author and doctoral candidate Kaitlyn Gayvert said context is vital. "A good example of this is chemotherapy," said Gayvert, who was named as one of Forbes' 30 Under 30 last year for her work on the project. "When treating advanced cancer, there is a higher bar for the types of side effects that doctors are going to allow."

She said this approach could improve the drug discovery pipeline, save money and save lives — but only if more data on toxicity results become available. After all, only 50 percent of clinical trial results are fully reported, Dr. Elemento said, adding that, "if we don't have data, we can't build these models."

By Syl Kacapyr

The mechanisms controlling how breast cancer develops, spreads to other parts of the body and responds to therapy remain poorly understood, but researchers from the Cornell University College of Engineering and Weill Cornell Medicine hope to change that through the Center on the Physics of Cancer Metabolism — a new multi-institutional translational research unit to be established with a National Cancer Institute grant.

On Aug. 25 New York Sens. Kirsten Gillibrand and Charles Schumer announced first-year funding for the center of $1.9 million. The grant could total $9.3 million over five years.

Dr. Lewis C. Cantley. Photo credit: Stephanie Diani

Led by Dr. Claudia Fischbach-Teschl, an associate professor of biomedical engineering at Cornell University, and Dr. Lewis Cantley, the Meyer Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, other partners include researchers from Memorial Sloan Kettering Cancer Center, the University of Texas MD Anderson Cancer Center and the University of California, San Francisco. The partnership will also foster collaborations across the Ithaca campus among researchers from the College of Engineering, the College of Arts and Sciences and the College of Veterinary Medicine.

The goal of the center is to combine the strengths of different interdisciplinary research groups to gain unprecedented understanding of the biological and physical mechanisms regulating how tumors function and metastasize, or spread, in the human body's microenvironment.

Dr. Cantley's expertise in cancer metabolism, which has led to several breakthroughs in the field, dovetail with Dr. Fischbach-Teschl's acumen in engineering of cancer models to enable the team to explore tumor development, progression and metastasis from a completely new perspective. Complemented by other investigators' expertise in micro- and nanofabrication, imaging and computational approaches, they can monitor and predict tumor metabolism and cell migration, and test drugs or other therapies in a patient-specific manner.

"The physical scientists in Ithaca are bringing technologies that don't exist here at Weill Cornell Medicine," Dr. Cantley said.

Dr. Fischbach-Teschl said teams in Ithaca will also benefit from access to patient samples and clinical knowledge that will be provided by Weill Cornell Medicine and other partners. The ultimate goal, she said, is to develop new therapeutic approaches to breast cancer, and eventually other types such as prostate and pancreatic cancer.

"Doing validation studies with patient-derived cells is always the end goal and we've done that, but we haven't done it as extensively because the resources are not there," Dr. Fischbach-Teschl added.

The center will focus on three main research areas over the next five years: the mechanisms that regulate tumor metabolism and how obesity affects the process; how membrane-surrounded vesicles produced by tumor cells affect their behavior; and the physical and metabolic constraints influencing tumor cell migration.

It will also provide an opportunity for next-generation scientists to receive unique interdisciplinary training, Dr. Fischbach-Teschl said.

"Students and postdocs in Ithaca are going to be trained in applying oncology principles to their engineering-focused study of cancer, and clinical trainees in New York City are getting exposed to the technologies and ideas that we develop here," she said.

Patients will benefit in another way as well: The inclusion of a patient advocacy component will link researchers directly to cancer patients and survivors to share emerging information about the disease with the people it is affecting. And adding the perspectives of patients will inform research approaches, ultimately leading to a more complete understanding of the disease.

"There's an opportunity to understand how to prevent metastasis from occurring, but even if we don't cure cancer, we're going to learn a lot from each other," Dr. Cantley said.

This story first appeared in the Cornell Chronicle.

Syl Kacapyr is public relations and content manager for the College of Engineering.

Weill Cornell Medical College student Abimbola Ayangbesan '18 has received the Ferdinand C. Valentine Medical Student Research Grant in Urology from The New York Academy of Medicine, which works to improve the health of people in New York City and cities across the world through its Institute for Urban Health.

The grant is awarded to as many as three medical students attending school in metropolitan New York who are committed to conducting basic or clinical research in urology over the summer. The academy provides a $4,000 stipend to support the students as they pursue 10- 12-week mentored research projects, the findings of which they will present at the Medical and Dental Student Forum on Aug. 18 in New York City.

"It's an honor to have been awarded the grant," said Ayangbesan, who first began urologic oncology research in bladder cancer patients the summer after his first year while working with Dr. Douglas Scherr, the Ronald Stanton Clinical Scholar in Urology and a professor of urology at Weill Cornell Medicine. "Having someone appreciate the undertaking of your project makes you believe you're moving in the right direction. It's motivation to keep on doing what I do."

Working with Dr. Scherr, Ayangbesan will examine a type of fatty tissue called white adipose tissue (WAT) to determine if it can be a potential biomarker for kidney cancer when inflamed. Previous research has shown that the presence of inflamed WAT in breast tissue in obese breast cancer patients has been associated with worse long-term prognoses than in patients who aren't obese; obese patients are at a higher risk of the disease returning and have a lower survival rate. Ayangbesan will be testing fatty tissue samples from patients with kidney cancer — a condition in which obesity is a risk factor — to determine if there is a similar connection that exists between inflamed WAT in kidney cancer patients and their long-term outcomes.

"The grant allows me the opportunity to continue my research in urology," Ayangbesan said, "and to further broaden my knowledge and attain better understanding of various urologic pathologies and morbidities."

By Jim Stallard

Even as researchers design more-potent new cancer therapies, they face a major challenge in making sure the drugs affect tumors specifically without also harming normal cells. This obstacle has thwarted many promising treatments.

Now, researchers from Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine have devised an innovative strategy for addressing this problem. Rather than aiming directly at cancer cells, they are focusing on targeting a molecule in the blood vessels that feed tumors and using nanotechnology to deliver tiny particles that will stick to the target and unleash their payload of cancer drugs. The researchers described this method in a study published June 29 and featured on the cover of Science Translational Medicine.

"We know that cancer cells in the blood can come into contact with P-selectin on blood vessel walls to stop them from circulating and to begin the formation of metastatic tumors," said Dr. Daniel Heller, a molecular pharmacologist at Memorial Sloan Kettering and an assistant professor of pharmacology and an assistant professor in the physiology, biophysics and systems biology program at the Weill Cornell Graduate School of Medical Sciences. "So in effect, we're hacking into the metastatic process in order to intercept the cells and destroy the cancer."

The target, a protein called P-selectin, serves as a kind of molecular Velcro for cancer treatments. It is especially prevalent in blood vessels that nourish cancer itself — including metastatic tumors, which cause roughly 90 percent of cancer deaths and are especially hard to treat.

"The ability to target drugs to metastatic tumors would greatly improve their effectiveness and be a major advance for cancer treatments," said lead author Dr. Yosi Shamay, a research fellow in Dr. Heller's laboratory at Memorial Sloan Kettering.

P-selectin: An Inviting Target for Nanoparticles

Scanning electron micrographs of P-selectin nanoparticles. Image credit: The Heller Laboratory

Dr. Heller's laboratory investigates the use of nanoparticles — tiny objects with diameters one thousandth that of a human hair — to carry drugs to tumors. The drugs are encapsulated within the nanoparticles, which must home in on a target within or near tumors to deliver the therapies effectively.

P-selectin emerged as an especially good target for cancer-focused nanoparticles because in addition to being found in tumor blood vessels, the molecule aids in the formation of metastases. When cancer cells leave a primary tumor and circulate in the blood, the cells can adhere to P-selectin, exit the blood vessel, and form a new tumor.

Exploring the Promise of Nanomedicine

Dr. Shamay made the nanoparticles out of a very abundant and cheap substance called fucoidan, which is extracted from brown algae that grows in the ocean. Fucoidan has a natural affinity for P-selectin, so the nanoparticle is simple to make and adapt.

"It's difficult to develop a nanoparticle-based treatment that is effective and safe in lots of people," Dr. Heller said. "You usually have to load both the drug and another component to the nanoparticle to enable the nanoparticle to bind to the correct spot — and any new element carries the potential to be toxic. But in this case, the nanoparticle itself is made of material that naturally attaches to the target.

"Just by targeting the tumor blood vessels, we found that the drug is going to the tumor itself and killing cancer cells directly," Dr. Heller added. "This makes the drugs delivered through this process work even better than we expected."

Even when the tumor blood vessels don't express P-selectin, the researchers could use radiation to trigger the expression of that protein in the tumor area before administering the nanoparticles. In collaboration with MSK radiation biologist Dr. Adriana Haimovitz-Friedman, they found that radiotherapy ensured that enough P-selectin was expressed for the nanoparticles to adhere to and deliver the therapy to the tumor.

The researchers conducted experiments showing that the nanoparticles selectively attached to cancer sites, including metastatic tumors, in the lungs of mice. The nanoparticles were filled with different cancer drugs, including chemotherapies and newer precision medicines that target specific molecules in cancer cells.

"We demonstrated that the drugs were more effective when administered within the nanoparticles than when given alone," Dr. Heller said. "We were able to give lower doses, which reduced the side effects."

In collaboration with the laboratory of MSK Physician-in-Chief Dr. José Baselga and cancer biologist Dr. Maurizio Scaltriti, Dr. Heller's lab used the nanoparticles to deliver a type of targeted therapy known as a MEK inhibitor, which has shown promise in several cancers. With this method, the MEK inhibitors were more effective against the tumors without causing the serious side effects, such as skin rashes, that have hampered many treatments.

"The clinical potential of nanomedicines for cancer has not been fulfilled, but targeting P-selectin with these nanoparticles is an approach that seems to be broadly useful for all kinds of drugs," Dr. Heller said. "This approach requires further in-depth testing, including clinical trials, but we are really excited about its promise."

Jim Stallard is a science writer for Memorial Sloan Kettering Cancer Center.

This story first appeared in Memorial Sloan Kettering Cancer Center's On Cancer blog.

By Tom Fleischman

Genetic mutations are a major cause of cancer, and tracking the role of each gene in cancer pathogenesis has long been an important tool in the fight against a disease that is expected to kill more than 1.6 million people this year.

The human colon model devised by researchers at Cornell and Weill Cornell Medicine recapitulated the main features of colorectal cancer progression, from in situ to invasion, in a matter of weeks.

Years ago, scientists developed the method of forward genetics – messages inserted into the genome of fruit flies to identify which genetic changes led to disease. The ability to perform the same type of study on human organs has, to date, been impossible, but a multi-institution collaboration – including researchers from Cornell and Weill Cornell Medicine – has published research on a tissue-engineering method that allows forward genetics screening on human tissue.

The paper, "A recellularized human colon model identifies cancer driver genes," was published July 11 in Nature Biotechnology. Dr. Michael Shuler, the Samuel B. Eckert Professor of Engineering and co-senior author of the paper, described his team's work as "powerful."

"You can't really do experiments very well on human tissue," he said, "so having a human system, which allows you to look at the genetics in the context of a controlled environment, is a fairly powerful technique."

The team created a human colon model by first deleting cells from normal human colon tissue, while retaining most of the molecules to which the cells adhere. The tissue is then repopulated with cells obtained from colonoscopy patient samples and from commercial sources.

"What you're really trying to do is provide a micro-environment that encourages the appropriate expression of the genes in the system," Dr. Shuler said.

Then, using a technique developed in the 1990s for inserting specific sequences of DNA into a genome – called a "Sleeping Beauty" transposon – the group tracked the genetic changes that occurred inside the colon model, which were consistent with typical early stage colorectal cancer (CRC).

Further testing confirmed that this recellularized colon model is capable of replicating key features of CRC progression. The work identified 38 driver (disease-carrying) genes, including six that had not been previously implicated in CRC progression.

Dr. Shuler admitted that while it's impossible to say the model provides an exact replica of CRC progression inside the body, "it gives you a human-based system to characterize some of the key steps in advance-stage colon cancer, and that is something that hasn't been possible."

The millimeter-scale model provides major tissue-relevant elements, including complex structure, cell-matrix interactions and physiological co-location of multiple types of differentiated cells.

Dr. Nancy Jenkins, professor of oncology at Houston Methodist Research Institute (HMRI) and co-senior author of the paper, said this technique will go a long way toward fulfilling an unmet need in cancer research.

"The recellularized human colon provides an exciting new model for identifying genes that are mutated during the earliest step in tumor metastasis," said Dr. Jenkins, a cancer geneticist. "Our hope is that a better understanding of the genetics of tumor metastasis will lead to better molecular targeted therapies and/or biomarkers for the treatment of colon cancer."

This study could lead researchers to pursue two directions, according to co-first author Dr. Joyce Chen, a former Cornell graduate student in biomedical engineering who is now a postdoctoral fellow working on a new set of problems in the lab of Dr. Harold Varmus, the Lewis Thomas University Professor at the Meyer Cancer Center at Weill Cornell Medicine.

"The first would be to improve our current colorectal tissue model and study the relationship with the immune system," she said. "We could also use this model to investigate the later stage of the disease, and the migration of cells out of the colon tissue and into other organs, such as the liver."

Other Cornell contributors included Jian Sun, research associate at Weill Cornell Medicine; Asmitta Bhattacharya, graduate student in the field of genetics, genomics and development; Pengcheng Bu, postdoctoral researcher in biomedical engineering; Lihua Wang, doctoral student in the field of biological and environmental engineering; and Shuibing Chen, assistant professor of chemical biology in surgery at Weill Cornell Medicine. Also contributing in writing the paper was Neal Copeland, professor of oncology at Houston Methodist Research Institute, and Zhubo Wei, a postdoctoral researcher in the lab of Jenkins and Copeland.

This work was supported by grants from the National Cancer Institute, the National Institutes of Health and the Cancer Prevention Research Institute of Texas.

Tom Fleischman is a physical sciences and engineering writer for the Cornell Chronicle.

CMS Oncology Care Model attracts almost twice the expected number of physician group practices

NEW YORK (June 30, 2016) — The Centers for Medicare & Medicaid Services (CMS) today announced that it has selected NewYork-Presbyterian, Columbia University Medical Center and Weill Cornell Medicine to participate in a care delivery model that supports and encourages higher quality, more coordinated cancer care. The institutions join nearly 200 physician group practices and 17 health insurance companies participating in the Medicare arm of the Oncology Care Model, which includes more than 3,200 oncologists and will cover approximately 155,000 Medicare beneficiaries nationwide.

"We are honored to be selected as participants in the Oncology Care Model," said Dr. Gary K. Schwartz, chief of hematology and oncology at NewYork-Presbyterian/Columbia University Medical Center. "With Vice President Biden's recent Moonshot Initiative, this comes at a pivotal point in cancer innovation and research. As a practicing physician, this initiative is a necessary approach to making cancer care as accessible and affordable as possible."

Cancer is one of the most common and devastating diseases in the United States: More than 1.6 million new cases of cancer will be diagnosed and cancer will kill an estimated 600,000 Americans in 2016. According to the National Institutes of Health, based on growth and aging of the U.S. population, medical expenditures for cancer in the year 2020 are projected to reach at least $158 billion (in 2010 dollars) - an increase of 27 percent over 2010. A significant proportion of those diagnosed are over 65 years old and Medicare beneficiaries.

"Cutting-edge scientific advancements are being made every day by our physicians, and nothing is more important than providing the very best, compassionate care at the greatest value to all patients," said Dr. David M. Nanus, chief of hematology and medical oncology at NewYork-Presbyterian/Weill Cornell Medical Center and Weill Cornell Medicine. "We remain committed to providing access to the highest quality care for patients with cancer, and this is one way we will achieve that vital goal."

The Oncology Care Model encourages practices to improve care and lower costs through episode- and performance-based payments that reward high-quality patient care. The Oncology Care Model is one of the first CMS physician-led specialty care models and builds on lessons learned from other innovative programs and private-sector models. As part of this model, physician practices may receive performance-based payments for episodes of care surrounding chemotherapy administration to Medicare patients with cancer, as well as a monthly care management payment for each beneficiary. The two-sided risk track of this model would be an Advanced Alternative Payment Model under the newly proposed Quality Payment Program, which would implement provisions from the Medicare Access and CHIP Reauthorization Act of 2015.

Practices participating in the five-year Oncology Care Model will provide treatment following nationally recognized clinical guidelines for beneficiaries undergoing chemotherapy, with an emphasis on person-centered care. They will provide enhanced services to beneficiaries who are in the Oncology Care Model to help them receive timely, coordinated treatment. These services may include:

• Coordinating appointments with providers within and outside the oncology practice to ensure timely delivery of diagnostic and treatment services;
• Providing 24/7 access to care when needed;
• Arranging for diagnostic scans and follow up with other members of the medical team such as surgeons, radiation oncologists, and other specialists that support the beneficiary through their cancer treatment;
• Making sure that data from scans, blood test results, and other tests are received in advance of patient appointments so that patients do not need to schedule additional visits; and
• Providing access to additional patient resources such as emotional support groups, pain management services, and clinical trials.

The names of those practices and payers participating in the Oncology Care Model, and more information about the model, can be found on the model's website: http://innovation.cms.gov/initiatives/Oncology-Care/. The Oncology Care Model begins on July 1, 2016 and runs through June 30, 2021.

As part of the Administration's "better care, smarter spending, healthier people" approach to improving health delivery, the Oncology Care Model is one of many innovative payment and care delivery models developed by the CMS Innovation Center and advanced by the Affordable Care Act. The Innovation Center is committed to transforming the Medicare, Medicaid and Children's Health Insurance Program (CHIP) programs and is expected to help deliver better care for individuals, better health for populations, and lower growth in expenditures for Medicare, Medicaid and CHIP beneficiaries.

NewYork-Presbyterian

NewYork-Presbyterian is one of the nation's most comprehensive healthcare delivery networks, focused on providing innovative and compassionate care to patients in the New York metropolitan area and throughout the globe. In collaboration with two renowned medical school partners, Weill Cornell Medicine and Columbia University College of Physicians & Surgeons, NewYork-Presbyterian is consistently recognized as a leader in medical education, groundbreaking research and clinical innovation.

NewYork-Presbyterian has four major divisions: NewYork-Presbyterian Hospital is ranked ? in the New York metropolitan area by U.S. News and World Report and repeatedly named to the magazine's Honor Roll of best hospitals in the nation; NewYork-Presbyterian Regional Hospital Network is comprised of leading hospitals in and around New York and delivers high-quality care to patients throughout the region; NewYork-Presbyterian Physician Services connects medical experts with patients in their communities; and NewYork-Presbyterian Community and Population Health features the hospital's ambulatory care network sites and operations, community care initiatives and healthcare quality programs, including NewYork Quality Care, established by NewYork-Presbyterian, Weill Cornell and Columbia.

NewYork-Presbyterian is one of the largest healthcare providers in the U.S. Each year, nearly 29,000 NewYork-Presbyterian professionals deliver exceptional care to more than 2 million patients.

For more information, visit www.nyp.org and find us on Facebook, Twitter and YouTube.

Columbia University Medical Center

Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. For more information, visit cumc.columbia.edu or columbiadoctors.org.

Weill Cornell Medicine

Weill Cornell Medicine is committed to excellence in patient care, scientific discovery and the education of future physicians in New York City and around the world. The doctors and scientists of Weill Cornell Medicine—faculty from Weill Cornell Medical College, Weill Cornell Graduate School of Medical Sciences, and Weill Cornell Physician Organization—are engaged in world-class clinical care and cutting-edge research that connect patients to the latest treatment innovations and prevention strategies. Located in the heart of the Upper East Side's scientific corridor, Weill Cornell Medicine's powerful network of collaborators extends to its parent university Cornell University; to Qatar, where Weill Cornell Medicine-Qatar offers a Cornell University medical degree; and to programs in Tanzania, Haiti, Brazil, Austria and Turkey. Weill Cornell Medicine faculty provide comprehensive patient care at NewYork-Presbyterian/Weill Cornell Medical Center, NewYork-Presbyterian/Lower Manhattan Hospital and NewYork-Presbyterian/Queens. Weill Cornell Medicine is also affiliated with Houston Methodist. For more information, visit weill.cornell.edu.

Men diagnosed with prostate cancer in the United States now have another treatment option: high-intensity focused ultrasound (HIFU). However, the jury is out in terms of the effectiveness of the treatment, according to Weill Cornell Medicine researchers. In a paper published June 28 in JAMA, they recommend that registries should be created to generate the data and evaluate cancer control and safety.

HIFU is a technique that blasts high-frequency ultrasound waves through the walls of the rectum, generating enough thermal energy to destroy prostate tissue. HIFU is designed to kill prostate cancer cells while keeping the gland intact, thus preserving urinary and sexual function. These benefits led prostate cancer survivors to liken the device to a "promise from heaven" at a recent U.S. Food and Drug Administration-sponsored workshop about HIFU, the authors noted in their paper.

"But this is still new," said lead author Dr. Jim Hu, the Ronald P. Lynch Professor of Urologic Oncology and a professor of urology at Weill Cornell Medicine, as well as a urologic oncologist at NewYork-Presbyterian/Weill Cornell Medical Center. "Although I believe that this therapy will be useful for some men preferring to avoid treatment of the entire prostate, it remains to be seen what the ideal patient and tumor characteristics are for HIFU."

While the FDA recently approved this form of treatment, which has been called a lumpectomy for men, for tissue ablation, HIFU has failed to gain approval as a treatment for prostate cancer. As a result, insurers won't cover HIFU, costing men who are treated with it approximately $25,000 out of pocket. 

Dr. Art Sedrakyan

"There's a lot of enthusiasm related to this technology. But the lack of data — particularly comparative information — is a major hurdle for regulatory and payment decisions," said co-author Dr. Art Sedrakyan, a professor of healthcare policy and research at Weill Cornell Medicine. Medicare and health insurance, for example, will not reimburse for HIFU unless the FDA specifically approved it for treating prostate cancer.

The authors examined studies conducted in the United Kingdom that assess HIFU's efficacy and found that only 50 percent of men achieved continence and potency preservation with the absence of cancer. But Dr. Hu says it's difficult to make head-to-head comparisons, as European men are often diagnosed with prostate cancer at later stages than those in the United States.

They also found that despite HIFU having a lower estimated cost compared to alternate treatments, such as robotic-assisted radical prostatectomy, its costs would most likely increase over time due to treatment failure, which could lead to repeat HIFU procedures and ultimately a switch to external radiation therapy or surgical treatments. However, "some men may find value in using HIFU to focally treat areas of prostate cancer and delay surgical or whole gland irradiation, which have greater risks of erectile dysfunction and urinary incontinence," Dr. Hu noted. "Additionally, men diagnosed with slow-growing cancers may find that HIFU is an ideal treatment to alleviate significant distress and anxiety. We know that a prostate cancer diagnosis is associated with depression and worse mental health and HIFU may alleviate these concerns."

"Our specific recommendation is that we need a registry where clinicians could contribute data, and this would allow us to do real-life evaluation of short-term and long-term outcomes," Dr. Sedrakyan said. Drs. Hu and Sedrakyan as well as partners from the Food and Drug Administration and the device manufacturers are hosting a meeting at the FDA on July 22 to develop a registry consisting of academic and community centers nationally.