Special Focus on Cancer Research News: A glance back and a gaze forward on glyco
July 2017
by Jeffrey Bouley  |  Email the author
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Special Focus: Cancer Research News
 
A glance back and a gaze forward on glyco
 
Looking at glycobiology with relation to cancer, plus more in recent oncology R&D news
 
Ah, synchronicity; it can be a wonderful thing. It was just a little over a year ago in June 2016 that we ran a special report, “An ever-evolving picture” by Randall C Willis, that looked deeply into the issue of cancer heterogeneity and how it can make therapy feel like whack-a-mole. Then exactly a year ago in the very next issue, another special report from Randy titled “Sweetening the pot” that asked (and to some degree answered) the question: Is improved understanding of glycobiology the secret to improved biologics?
 
That glycobiology report also touched on heterogeneity as it can relate to glycans, among other issues—and one of those other issues was the growing role of glycobiology in cancer research, with the report noting at one point, for example: “While many glycans may actively participate in cancer, influencing processes like tumor proliferation, invasion and metastasis, others are components of glycoproteins currently being used as biomarkers of disease, such as prostate-specific antigen, alpha-fetoprotein, carcinoembryonic antigen and MUC-1. The glycosylation state of these proteins is significantly altered in cancer.”
 
So, with those “anniversaries” in mind, and as preparation for this latest installment of our cancer research news special coverage heated up, it was a nice surprise to see June news from GlycoMimetics—a clinical-stage biotech that uses novel and proprietary glycobiology technology to develop treatments for diseases, especially those with high unmet needs like sickle cell disease and cancer—announcing new and updated data from the company’s Phase 2 portion of its ongoing Phase 1/2 clinical trial that showed high remission and low mortality rates of its drug candidate GMI-1271, an E-selectin antagonist being developed as a treatment for patients with acute myeloid leukemia (AML).
 
The announcement coincided with GlycoMimetics clinical investigators presenting the data that very day from 79 patients in the trial via posters and discussion at the 2017 annual meeting of the American Society for Clinical Oncology (ASCO) in Chicago.
 
In the trial, patients treated with GMI-1271 together with standard chemotherapy had continued to achieve higher than expected remission rates based on historical controls, as well as lower than expected induction-related mortality rates, with the treatment continuing to be well tolerated in this patient population, according to the company.
 
“We are excited to share this promising new data for GMI-1271, which continue to support the potential for this new drug candidate to treat AML, a disease that has often eluded medical interventions thus far,” said Rachel King, CEO of GlycoMimetics. “We are increasingly optimistic that GMI-1271 may help address unmet needs in this and other cancers.”
 
Among the 54 relapsed/refractory AML patients participating in the trial for whom data was available:
  • The overall response rate (complete remission/complete remission with incomplete marrow recovery, or CR/CRi) was 41 percent, which is higher than historical controls, and the 60-day induction-related mortality rate was 7 percent, which is lower than historical controls.
  • Oral mucositis, or inflammation with mouth ulcers that is a sign of adverse effects of chemotherapy, was seen at low rates and severity, with only one grade 3/4 event observed.
  • The median overall survival time for Phase 1 trial patients was 7.6 months.
  • Remissions were durable enough to allow nine patients to receive stem cell transplants.
  • For patients in the Phase 1 portion of the trial who responded with a remission, more than half survived for at least a year after treatment.
Among the 25 newly diagnosed elderly patients (age 60 and older) participating in the trial for whom data was available:
  • The overall response (CR/CRi) rate was 68 percent, with 73 percent in patients with de-novo AML and 64 percent in patients with secondary AML.
  • The 60-day mortality rate was 8 percent.
  • There were no cases of grade 3 or 4 mucositis.
  • For the nine evaluable patients achieving CR/CRi, disease-free survival was 100 percent at six months after treatment.
“These results are very encouraging, indicating that the E-selectin antagonist may enhance our ability to improve the complete remission rate and potentially to improve the tolerability of intensive chemotherapy for patients with acute myeloid leukemia,” said Dr. Daniel J. DeAngelo, the trial’s lead investigator, who serves as that Dana-Farber Cancer Institute’s director of clinical and translational research for adult leukemia and as an associate professor of medicine at Harvard Medical School. “We look forward to continuing our clinical testing of GMI-1271 and further examining its potential for improving outcomes for patients with AML.”
 
Data from the Phase 1/2 trial were submitted to the U.S. Food and Drug Administration (FDA). In May 2017, the FDA granted GMI-1271 Breakthrough Therapy designation for treatment of adult patients with relapsed/refractory AML. In addition, GMI-1271 has been granted Orphan Drug designation and Fast Track status by the FDA and Orphan Drug designation by the European Commission.
 
And while we’re on the topic of glycobiology, we thought we’d share some news from a few companies offering technology for that area of research, whether it be for cancer or for other diseases more traditionally associated with glycans.
 
Essential Pharmaceuticals
 
In June, Essential Pharmaceuticals LLC’s chief science officer, Dr. Adam Elhofy, discussed mechanisms to increase antibody titer and presented new data on Cell-Ess Universal Titer Boost at the BIO International Convention in San Diego and at the Cell Culture & Cell Therapy: Bioprocessing Conference in Philadelphia—with an eye firmly toward the issue of increasing antibody titer without impacting glycosylation.
 
According to the company, Cell-Ess is the world’s first universal titer boost and enhancer that works across a wide range of media systems and, when used as a feed, improves consistency in glycan patterns while increasing protein titer by 20 to 50 percent compared to control in various previously optimized cell lines and media schemes.
 
“Our findings confirm numerous previous studies that Cell-Ess increases protein titer and productivity in multiple cell lines and media systems,” said Elhofy. “Additionally, this new data demonstrates that Cell-Ess simultaneously improves consistency of glycosylation patterns and increases the amount of higher glycoforms or galactosylation.”
 
ProZyme
 
Also in June, ProZyme Inc., a manufacturer of reagents and tools for glycobiology, announced the launch of the Gly-X N-Glycan Rapid Release and Labeling with 2-AB Express and Gly-X N-Glycan Rapid Release and Labeling with InstantAB kits. Both kits leverage ProZyme’s next-generation Gly-X platform that provides a simplified in-solution workflow for N-glycan analysis.
 
“We are pleased to introduce two additions to ProZyme’s Gly-X offering,” said Dr. Sergey Vlasenko, president and CEO of ProZyme. “We developed the Gly-X platform to speed up glycan sample preparation, but two very commonly used labels, 2-AB and InstantAB, have been missing. With the launch of the Gly-X 2-AB Express and Gly-X InstantAB kits, analytical and QC groups at biopharma companies can simplify their processes and get the N-glycan results faster. In addition, the use of well-established labels will assure data continuity and enable easier platform transition for ongoing projects.”
 
Thermo Fisher Scientific
 
We’d be remiss if we didn’t also mention the Applied Biosystems GlycanAssure Glycan Analysis and Quantitation System from Thermo Fisher Scientific, which we covered in the magazine late last year in our Products & Services section. This high-throughput, high-resolution glycan analysis workflow is said to be a highly sensitive system for N-glycan analysis that offers simple and easy magnetic bead-based sample preparation with multiple dyes for fluorescent labeling, as well as parallel processing and data analysis of 96 samples in seven to nine hours.
 
According to Thermo, the system is the first glycan analysis platform that combines both throughput and data quality. The GlycanAssure System, the company says, offers an integrated glycan analysis platform that helps save labor, time and cost of analysis, and assay-specific software reportedly ensures fast data analysis and reporting.
 
So, now that we’ve reminisced about glycobiology, updated you and tied it back to our oncology coverage recently at DDNews, read on to see what other stories of cancer research news—outside the area of glycans—that this special focus section has to offer you.
 

The birthplace of cancer metastases?
 
TSRI researchers in California find surprising source of tumor cells, plus oncology news from the Florida campus
 
LA JOLLA, Calif.—Scientists at The Scripps Research Institute (TSRI) believe they have discovered why some cancers may reoccur after years in remission. The findings, published recently in the journal Cell Reports, show that invasive tumors can begin sending out tumor cells far earlier than previously thought. These escaping cells—which can enter the bloodstream before the primary tumor is detected—may seed secondary tumors that don’t show up for years.
 
Importantly, the scientists demonstrated that the escaping tumor cells reach the bloodstream by entering blood vessels deep within the dense tumor core, upending the long-held belief that metastatic cells come from a tumor’s invasive borders.
 
“The actual process of cancer cell dissemination via hematogenous routes is a relatively under-studied process, but we finally have an answer as to where it takes place,” said Elena Deryugina, a TSRI assistant professor who led the study in a long-term collaboration with TSRI staff scientist William Kiosses.
 
Using cancer cell lines generated from human fibrosarcoma and carcinoma tumors, the researchers found that primary tumors can send out cells early on, independent of cancer invasion into adjacent tissue. This could explain why doctors often see secondary tumors appearing earlier than they would have predicted.
 
This finding may also shed light on why patients with early-stage tumors still have a risk of developing metastatic disease, according to Deryugina, who says: “These metastases may have been seeded when the primary tumor was even too small to be visualized.”
 
Peering through dense primary tumors had been a roadblock in cancer studies until now, and this new discovery was possible because the researchers developed animal models that allowed for microscopic analysis of tumor cell dissemination. Specifically, adapted mouse ear and chick embryo models let the scientists examine developing tumors through relatively thin tissue layers.
 
The new study is also the first to examine entire tumors to find out exactly where escaping cells come from. The scientists tagged human tumor cells with a florescent protein to distinguish them from the cells of a tumor-bearing animal. Using high-resolution confocal microscopy techniques spearheaded by Kiosses, the researchers mapped in 3D all blood vessels across entire tumors, from the tumors’ dense cores to their invasive tendrils.
 
The researchers mapped the location of every tumor cell relative to the center of the closest blood vessel—or visualized within blood vessels. This approach gave the researchers a way to finally analyze the escape process, called intravasation, and to demonstrate where intravasating cells enter blood vessels.
 
And that was where they got their surprise finding that the vast majority of tumor cells entered blood vessels within the tumor core, not in the invasive tendrils. In fact, the researchers found that fewer than 10 percent of escaped cells intravasated from the stroma-invading sprouts.
 
The researchers also found that levels of the protein EGFR could be a good indicator of whether tumor cells would intravasate. EGFR appeared to regulate a tumor’s ability to induce blood vessels that support cancer cell escape. “Therefore, the data indicate the importance of harnessing the EGFR activity early on in cancer patients,” said Deryugina.
 
Next, the researchers plan to investigate the functional roles of different cell types within a primary tumor, such as inflammatory leukocytes, which also may be critically important for supporting intratumoral cancer cell intravasation.
 
Meanwhile, across the country at the other coast and TSRI’s Florida campus, scientists there—with help from researchers at the University of California, San Diego, and the University of Illinois—found this spring that two immune system molecules may be key to the development of drug resistance in estrogen-driven breast cancers, a finding that could lead to novel therapeutic approaches. These molecules, which are cytokines called interleukin 1 beta (IL1β) and tumor necrosis factor alpha (TNFα), had previously been linked to the spread of drug-resistant cancer, but scientists were unsure of the exact mechanisms that led these molecules to drive drug resistance.
 
The new study, published by the journal Molecular Cell, reveals that IL1β and TNFα turn on pathways that modify the actual shape of the estrogen receptor. This phenomenon appears to drive resistance to the common anti-cancer drug tamoxifen.
 
“Cytokines change the shape of the estrogen receptor, and that change overrides the inhibitory effects of tamoxifen and leads to drug resistance,” said Kendall Nettles, a TSRI associate professor who led the new study alongside senior author Christopher K. Glass and study first author Joshua D. Stender of UC San Diego. “These findings dramatically alter our understanding of the biological actions of pro-inflammatory cytokines in breast cancer cells.”
 
Using a combination of genomic, cellular, biochemical and structural approaches, the researchers found that the way these cytokines alter the estrogen receptor are sufficient to induce growth of breast cancer cells in the absence of estrogen, precisely what happens when breast cancer is initially treated with an endocrine therapy like tamoxifen. Scientists found that in addition to reversing tamoxifen suppression of growth, cytokine activation of the estrogen receptor also enhanced the invasive properties of a specific line of human breast cancer cells known as MCF-7, the most studied human breast cancer cells in the world.
 
Nettles pointed out that both inflammation and immune cells are known causes of resistance, but if that inflammation can be blocked, resistance can be reduced or eliminated.
 
“These tumors can reprogram the immune cells to their advantage so that the cells become tumor-supportive,” Kettles said. “We think we can produce hormone therapies that can, in essence, re-reprogram the immune system or prevent it from altering the receptor in the first place, which is an obvious strategy for blocking these adverse effects. Importantly, our atomic snapshot of the receptor showed that the same mechanism can explain how Her2Neu or other growth-promoting factors, as well as certain invasion and motility signals. also cause resistance to anti-hormone therapies.”
 
Also in the spring, TSRI’s Florida scientists developed a new drug delivery method involving antibody-drug conjugates (ADCs) that produces strong results in treating cancers in animal models, including some hard-to-treat solid and liquid tumors, as part of a study led by TSRI associate professor Christoph Rader and published by Cell Chemical Biology.
 
On their own, Rader noted, antibodies are usually not potent enough to eradicate cancer. However, their high specificity for antigens makes them ideal vehicles for drug delivery straight to tumor cells.   
 
“We now show for the first time that selenomab-drug conjugates, which are ADCs that utilize the unique reactivity of selenocysteine for drug attachment, are highly precise, stable and potent compositions and promise broad utility for cancer therapy.”
 
Along with its potency, Rader noted, the ADC’s stability is critical to its effectiveness. The researchers found that their new ADCs showed excellent stability in human blood in vitro and in circulating blood in animal models. Moreover, the new ADCs were highly effective against HER2 breast cancer, a particularly difficult cancer to treat, and against CD138 multiple myeloma. Importantly, the ADCs did not harm healthy cells and tissues.
 
“The selenomab-drug conjugate significantly inhibited the growth of an aggressive breast cancer,” said TSRI research associate Xiuling Li, first author of the study. “Four of the five mice tested were tumor-free at the end of the experiment, a full six weeks after their last treatment.”
 
The researchers plan to investigate similar ADCs going forward. Rader, along with TSRI professor Ben Shen, was recently awarded $3.3 million from the National Cancer Institute to test highly cytotoxic natural products discovered in the Shen lab using selenomabs as drug delivery vehicles.
 

More than 240 immuno-oncology treatments now in development
 
WASHINGTON, D.C.—A new report, titled “Medicines in Development for Immuno-Oncology” and released in June by the Pharmaceutical Research and Manufacturers of America (PhRMA)  in partnership with the American Cancer Society Cancer Action Network (ACS CAN), finds there are more than 240 immuno-oncology medicines and vaccines currently in development.
 
As the partners note, “Research into the role of the body’s immune system in fighting cancer has yielded some of the most exciting new advances, resulting in a new wave of immunotherapies specifically targeting cancers.”
 
While there is no single established definition of immuno-oncology, they say, their report includes many of the most recognized classes: adoptive cell therapies (including CAR-T therapy), bi-specific antibodies, cytokines, immune checkpoint modulators, oncolytic virus therapies and vaccines.
 
“Cancer continues to be one of the most complex and vexing diseases of our time, and it will impact an estimated 1.6 million Americans who will be diagnosed this year,” said Stephen J. Ubl, president and CEO of PhRMA. “As our understanding of the root causes of cancer grows, we are expanding the types of treatments we are able to bring to patients. The idea of harnessing the body’s own immune system to fight cancer is not new, but recent breakthroughs are making it a reality, bringing hope to patients.”
 
“We are at a moment of tremendous opportunity when it comes to developing therapies that can address even the most vexing cancers we see today,” added Chris Hansen, president of ACS CAN. “To fully leverage our potential to reduce suffering and death from cancer, robust and sustained federal investment in basic research is critical to provide the necessary building blocks that, together with privately funded innovation, lead to advances in immunotherapy and other targeted treatments.”
 

A path for tackling rare cancers
 
Study results indicate importance of treatment based on genetic mutation rather than location of origin
 
NEW YORK—An international team of scientists led by the Icahn School of Medicine at Mount Sinai and the University of Connecticut (UConn) School of Medicine have reported the results of a genome sequencing study for an extremely rare form of cancer. Their findings demonstrate the utility of this approach to open the door for therapy options for rare diseases that are neglected due to scarcity of patients or lack of resources. The paper, “Genomic profiling reveals mutational landscape in parathyroid carcinomas,” was published by JCI Insight, a journal of the American Society for Clinical Investigation.
 
For this project, leading genomic scientists performed exome sequencing on tumors and matched normal samples from 17 patients with parathyroid carcinoma, an ultra-rare form of cancer for which there is no effective treatment. When a tumor forms on one of the four small parathyroid glands located behind the thyroid, it can impact the body’s control of calcium levels in both blood and bones. Patients with this cancer, if it is not cured early by surgery, typically die from its progressive metabolic complications including very high blood calcium levels, weakened bones and calcium-induced kidney damage.
 
The study combined the power of UConn’s expertise in parathyroid disease and other endocrine tumors with Mount Sinai’s leadership in next-generation genomic sequencing and bioinformatics analysis, along with key contributions from the global consortium they organized.
 
Researchers found several mutations in known cancer-related genes and pathways, including the CDC73 tumor suppressor, the PI3K/AKT/mTOR pathway and the Wnt canonical pathway, among others. This in-depth characterization provides a clear view of genetic mechanisms involved in parathyroid carcinoma and could lead to the first therapy options for patients.
 
“This is the largest genomic sequencing study to date for this rare and deadly cancer, and we believe it serves as important validation for using this approach to uncover clinically relevant information in any number of neglected diseases,” said Rong Chen, senior author of the paper and assistant professor in the Department of Genetics and Genomic Sciences at Mount Sinai. “Genomic analysis is opening the doors to diseases that could never have been understood through traditional biomedical research because there simply aren’t enough patients to observe.”
 
The genetic variants identified in this study have been detected in other cancers and are the subject of ongoing basket trials, or clinical trials focused on specific mutations rather than the tissue where the cancer formed.
 
Mount Sinai’s use of its latest cutting-edge genomics techniques helped build upon the findings of co-senior study author Dr. Andrew Arnold of UConn and his research team, which were published in the New England Journal of Medicine in 2003: discovering the first gene in non-familial parathyroid cancer. Arnold’s team has a longstanding history of investigating the molecular genetic underpinnings of endocrine gland tumors, being the first to also discover cyclin D1 (PRAD1), a key regulator in multiple cancers including breast cancer, which turns out in the present study to be altered in parathyroid carcinoma as well.
 
“Some of the tumor-specific genomic vulnerabilities we found turn out to be shared with much more common cancers, so drugs already being developed for other cancers may prove valuable in parathyroid cancer. This offers new hope for our patients, and serves as a model for approaching other rare and neglected diseases,” said Arnold, the study’s co-leader, who serves as the Murray-Heilig Chair in Molecular Medicine, director of the Center for Molecular Medicine and chief of endocrinology at UConn School of Medicine.
 
“As we generate and analyze large, multidimensional data sets from tumors, there is mounting evidence that cancer treatment may be more successful when based on specific genetic markers instead of tissue of origin,” said Dr. Eric Schadt, senior author on the paper and the Jean C. and James W. Crystal Professor of Genomics at the Icahn School of Medicine at Mount Sinai, as well as founding director of the Icahn Institute for Genomics and Multiscale Biology. “Conventional wisdom tells us that the only way to treat rare disease is to invest billions of dollars in developing new therapies. This study shows that parathyroid carcinoma may be rare but its genetic mutations are not, indicating that patients may benefit right now from treatments that are already on the market.”
 

Tethered nanoparticles make tumor cells more vulnerable
 
CAMBRIDGE, Mass.—Massachusetts Institute of Technology (MIT) researchers have devised a way to make tumor cells more susceptible to certain types of cancer treatment by coating the cells with nanoparticles before delivering drugs.
 
By tethering hundreds of tiny particles to the surfaces of tumor cells in the presence of a mechanical force, the researchers made the cells much more vulnerable to attack by a drug that triggers cancer cells to commit suicide, notes MIT News’ Anne Trafton. It appears that the tethered nanoparticles increase the forces exerted on the cells by flowing blood, which makes the cells more likely to die.
 
“When you attach many particles to the membranes of these cells, and then expose them to forces that mimic those in the human body, like blood flow, these therapeutics become more effective. It’s a way of amplifying the forces on the cells using polymeric materials,” says Michael Mitchell, a postdoc at MIT’s Koch Institute for Integrative Cancer Research and the lead author of the study.
 
In tests in mice, the researchers found that the tethered nanoparticles made the cell-suicide-inducing drug 50 percent more effective, and this combination eliminated up to 90 percent of tumor cells in the mice.
 
In the new study, the MIT team set out to determine whether physical forces such as those exerted by blood flow might influence how tumors respond to drug treatment. They focused on an experimental drug known as TRAIL, which is a protein expressed on different cells of the immune system. TRAIL is a member of a family of tumor necrosis factors that bind to death receptors on cell membranes, sending them a signal that stimulates apoptosis, or programmed cell death.
 
Initial experiments revealed that tumor cells became more susceptible to this drug after being exposed to shear forces from physiological fluids. “Under these flow conditions, more tumor cells began to die in the presence of the therapeutic,” Mitchell says.
 
That led the researchers to hypothesize that they could make cells even more susceptible to the treatment by increasing the forces acting on them. One way to do that is to attach tiny particles to the cell surfaces. Acting like balls on a string, the tethered particles batter and tug at the tumor cell surface as blood flows by, making the cells more susceptible to the cell death signal from the drug.
 
The particles, which can be injected into the bloodstream, are made of biodegradable polymers known as PLGA. These particles are coated with another polymer, PEG, that is tagged with a ligand or antibody specific to proteins found on tumor cell surfaces, which allows them to be tethered onto the surface.
 
In tests in mice, the researchers found that attaching particles to tumor cells and then treating them with TRAIL killed metastatic tumor cells in the bloodstream and also reduced the progression of solid tumors in mice. The researchers tested particles ranging from 100 nanometers to 1 micrometer and found that the largest ones were more effective. Also, as greater numbers of particles were tethered to the surface, more cells died.
 
The effect of the treatment appears to be specific to tumor cells and does not induce apoptosis in healthy cells, the researchers say.
 

Cell-penetrating antibodies to oncogenic RAS show antitumor activity
 
DAEJEON, South Korea—The genes of the RAS family are the most commonly mutated oncogenes, involved in approximately 30 percent of all human cancers, but have resisted drug discovery efforts for more 30 years. According to Orum Therapeutics, data published recently in Nature Communications brings researchers a step closer to developing a drug that targets RAS.
 
RAS proteins function to transmit signals within cells that control cell growth, differentiation and survival, and mutations found in human cancers result in RAS being constitutively activated. In addition to playing a role in tumor formation, tumors containing activating RAS mutations are often aggressive and do not respond to current therapies, including drugs targeting EGFR.
 
“Discovered nearly 35 years ago, the mutant RAS protein has been considered a highly-validated cancer drug target, but also has a reputation as being undruggable,” said Dr. Yong Sung Kim, principal investigator on the paper, co-founder of Orum Therapeutics and a professor in the Department of Molecular Science and Technology at Ajou University in Korea.
 
The paper published by scientists at Ajou University and Orum Therapeutics, titled “Antibody targeting intracellular oncogenic Ras mutants exerts anti-tumor effects after systemic administration,” describes the preclinical characterization of a novel monoclonal antibody, called RT11-i, designed to be internalized by the cell and to directly target the activated form of RAS. The data show that RT11-i binding is specific to activated RAS, binds these proteins inside the cell and blocks interactions with effector proteins, resulting in inhibition of downstream oncogenic signaling. When given to tumor-bearing mice, RT11-i inhibited tumor growth in several xenograft models and was shown to be well tolerated.
 
“This data shows that with our cell penetrating antibody technology, we now have the ability to selectively inhibit activated RAS to achieve anti-tumor activity with a systemically administered monoclonal antibody,” Kim explained. “Additional data suggests the combination of RT11-i and an anti-EGFR therapy might be an effective clinical strategy for patients with advanced colon cancer who have oncogenic RAS mutations.”
 
When tested in xenograft models of human cancer, RT11-i had preferential accumulation in tumor tissue and demonstrated measureable antitumor activity in mice where the tumor contained an activating RAS mutation. In addition, in a xenograft mouse model of colorectal cancer resistant to cetuximab, which targets EGFR, co-adminstration of cetuximab and RT11-i was shown to overcome resistance to cetuximab.
 
“As an anticancer therapy, our cell penetrating antibodies are easy to produce, allow for systemic administration that is well tolerated, and have desirable pharmacological properties,” said Dr. Sung Joo Lee, co-founder and CEO of Orum Therapeutics. “We believe this could be a very important first-in-class therapeutic for hard-to-treat pancreatic, colon and non-small cell lung cancers.”
Code: E071731

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