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Cancer Research News Focus Feature: Oncology--Stem to stern
December 2019
by Jeffrey Bouley  |  Email the author
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Cancer Research News Focus Feature
 
Oncology: Stem to stern
A look at gastroesophageal, gastric and colorectal cancer progress
 
By Jeffrey Bouley
 
As is often the case, we like to start these cancer-themed Focus Features with an article on a set of related subjects, and this time we are going to follow cancer from the throat all the way to—well, the other end, with trial data from Zymeworks for gastroesophageal adenocarcinoma treatment, news of a grant to City of Hope to study an oncolytic virotherapy in gastric cancer and research from the Salk Institute on how a colorectal cancer drug actually works.
 
Promising Phase 1 data for ZW25 in combination with chemotherapy
BOSTON—Zymeworks Inc., a clinical-stage biopharmaceutical company, recently announced the first data from its Phase 1 study evaluating the novel bispecific antibody ZW25 for gastroesophageal adenocarcinoma (GEA).
 
“Today we report the promising antitumor activity of ZW25 in combination with chemotherapy for people with HER2-expressing GEA,” said Dr. Diana Hausman, chief medical officer at Zymeworks. “These results compare favorably with current standard of care treatments for patients who have progressed after first-line therapies, including trastuzumab and chemotherapy. The data further support the prioritization of our ongoing Phase 2 trial of ZW25 plus chemotherapy as a first-line treatment for GEA and our goal of establishing ZW25 as the new best-in-class therapy for people with HER2‑expressing cancers.”
 
The FDA has granted Fast Track designation to ZW25 for first-line HER2-positive GEA in combination with standard of care chemotherapy, and a Phase 2 trial evaluating combination treatment in this setting is actively enrolling patients.
 
“The patients in this Phase 1 study have a difficult-to-treat, advanced stage of cancer, which has progressed despite multiple prior therapies,” noted Dr. Funda Meric-Bernstam, chair of the Department of Investigational Cancer Therapeutics and medical director of the Institute for Personalized Cancer Therapy at The University of Texas MD Anderson Cancer Center. “The preliminary activity and tolerability of ZW25 combination treatment with paclitaxel or capecitabine brings hope to these patients and warrants further investigation in a first-line setting.”
 
The results came from part three of an ongoing Phase 1 study present the safety and efficacy of ZW25, at the recommended dose of 20 mg/kg every other week, in combination with paclitaxel or capecitabine as a treatment for 14 patients with heavily pretreated HER2-expressing GEA. Patients received a median of 2.5 prior systemic therapies, and 93 percent had progressed following trastuzumab treatment.
 
Nine of 14 patients were response-evaluable. Overall, the majority of patients experienced a decrease in their target lesions with a disease control rate of 78 percent, comprising five (56 percent) partial responses and two (22 percent) stable disease. These responses were observed in both low and high HER2-expressing GEA. At the time of the data cut-off, four of the five partial responses had been confirmed, and five (56 percent) response-evaluable patients were still on study.
 
The overall safety profile of ZW25 plus chemotherapy was similar to that seen with chemotherapy alone. The most common treatment-related adverse events occurring in two or more patients were primarily grade 1 or 2 and manageable with symptomatic treatment.
 
ZW25 is being evaluated in Phase 1 and Phase 2 clinical trials across North America and South Korea. It is a bispecific antibody, based on Zymeworks’ Azymetric platform, that can simultaneously bind two distinct locations on HER2, known as biparatopic binding. This unique design results in multiple mechanisms of action including dual HER2 signal blockade, increased binding and removal of HER2 protein from the cell surface, and potent effector function leading to encouraging antitumor activity in patients.
 
City of Hope researchers receive U.S. DoD grant to study CF33
SYDNEY, Australia & DUARTE, Calif.—Australia-based Imugene Ltd., a clinical-stage immuno-oncology company, announced in late October that prominent City of Hope researchers Dr. Yanghee Woo and Dr. Yuman Fong in the United States had received a roughly $385,000 grant from the U.S. Department of Defense (DoD) titled “Discovery of Immune Biomarkers That Predict Response to a Novel Chimeric Immuno-Oncolytic Virus Encoding Anti-PD-L1 in Gastric Cancer Peritoneal Carcinomatosis.”
 
The DoD grant focuses on the area of gastric cancer (GC), a disease that disproportionately affects U.S. military service members, veterans, and their beneficiaries who have increased exposure to hazardous environmental risk factors, such as H. pylori, Epstein-Barr viral infections, radiation and tobacco smoking. Peritoneal carcinomatosis (PC) is a fatal evolution of GC for which there is no effective treatment. Across military families and the general population, over 60 percent of all patients with GC will develop peritoneal disease as the most common manifestation of recurrence or metastatic presentation.
 
The progression of primary stomach cancer to PC is facilitated by the unique peritoneal tumor microenvironment, where metastatic peritoneal seeding requires evasion of antitumor immunity and maintenance of a highly immunosuppressive microenvironment. The researchers rationalize that a combined approach using Imugene’s proposed license for novel oncolytic virus CF33 armed to express an anti-PD-L1 antibody as immune modulator could specifically kill cancer cells, convert the immunologically “cold” environment of PC into a “hot” environment and enhance overall efficacy of GC therapy.
 
Oncolytic virotherapy (OV) utilizes naturally occurring or genetically modified viruses to infect, replicate in and kill cancer cells, while sparing healthy cells. The first OV for human therapy—Amgen’s T-VEC (talimogene laherparepvec) for the treatment of metastatic melanoma—was recently approved by the U.S. Food and Drug Administration. Imugene notes as well that, interestingly, many cancer cell characteristics that lead to chemotherapy resistance and radiation resistance enhance the success of oncolytic virotherapy.
 
C33 is a chimeric poxvirus derived through recombination among multiple strains of vaccinia virus and other species of poxvirus, thus it is reportedly better than a virus based on a single strain. Preclinical data has demonstrated that CF33 is more efficacious than all parental viruses and some viruses in clinical trials.
 
According to Imugene, CF33 efficiently shrank injected tumors and distant non-injected tumors in human triple-negative breast cancer, colon cancer, ovarian cancer xenograft models in mice without adverse effects at a dose that is two to five orders of magnitude lower than doses used for oncolytic viruses under clinical testing. “Especially impressive is that CF33 can shrink multiple types of cancer at an extremely low dose (1000 PFU),” the company said in a news release. “Importantly, CF33 shrinks not only injected tumors, but also non-injected distant tumors (abscopal effect).”
 
Salk scientists uncover mechanism of colorectal chemotherapy drug
LA JOLLA, Calif.—Colorectal cancer is a common lethal disease, and treatment decisions are increasingly influenced by which genes are mutated within each patient. Some patients with a certain gene mutation benefit from a chemotherapy drug called cetuximab, although the mechanism of how this drug worked was unknown.
 
Salk scientists have combined computational biology with experimental investigations to discover, for the first time, the mechanism for why these patients respond to cetuximab, which will help doctors identify more effective, targeted treatment plans for people diagnosed with colorectal cancer. The findings were published in Science Signaling on Sept. 24 and demonstrate the power of blending computational and experimental approaches as well as how foundational scientific research can translate to an immediate impact for patients.
 
“This study has direct clinical implications because now doctors can start prescribing this effective drug to colorectal cancer patients with this mutation immediately,” said Edward Stites, senior author of the paper and an assistant professor in the Integrative Biology Laboratory. “The work also highlights the necessity of mathematical models based on fundamental biochemistry as a tool for understanding the behaviors of biological networks that are relevant to disease.”
 
Approximately 40 percent of patients with colorectal cancer have a mutated KRAS gene in cells in their tumors. Most KRAS mutants cause the patient not to benefit from cetuximab. Patients with the KRAS G13D mutation are exceptions and have appeared to respond to cetuximab, but the mechanism of action has not been apparent so this drug is not commonly used on these patients. Doctors are hesitant to prescribe a drug without a known mechanism due to possible interaction with other medications or unforeseen side effects.
 
“Our goal was to elucidate a mechanism for why tumors that harbor KRAS G13D mutations are sensitive to cetuximab,” explained Thomas McFall, first author on the paper and a postdoctoral fellow in the Stites lab. “Understanding this mechanism will aid doctors in receiving insurance support for prescribing cetuximab, which could benefit upwards of 10,000 colorectal cancer patients per year.”
 
To understand why KRAS G13D tumors responded to cetuximab, the researchers first used computational models to simulate complex reactions and tease out biochemical differences between healthy and mutant genes based on the biochemical understanding of each process and previous clinical trial data. This told them where to look in their laboratory tests to identify and quantify the molecular mechanism that explains why KRAS G13D patients respond differently. The researchers replicated their findings across three genetically distinct cell lines to demonstrate the reliability of the results.
 
In a cell with no KRAS mutations, a known tumor suppressor called neurofibromin keeps healthy KRAS proteins well-behaved. But most KRAS mutations are overly active and cannot be controlled by neurofibromin. When mutated KRAS is present, neurofibromin attempts to control the mutant KRAS at the expense of controlling the healthy KRAS.
 
Furthermore, the scientists discovered that even though KRAS G13D is overly active, it is doing so without neurofibromin being aware. Thus, neurofibromin can still keep the healthy KRAS under control. Additionally, the researchers demonstrated that cetuximab will only work to suppress tumors as long as there is neurofibromin available to suppress the activity of healthy KRAS.
 
“This work demonstrates the power of computational systems biology approaches to address problems in personalized medicine,” said Stites. “Doctors could sequence the gene to find out if the patient has this KRAS G13D variant, and if they do, then doctors could confidently prescribe cetuximab. That’s important, because it will give many cancer patients a new treatment option.”
 
Next, the authors plan to examine the mechanisms of more KRAS gene mutation variants that do not bind to neurofibromin, as patients with these variants may also benefit from taking cetuximab.
 
Study shows how circulating tumor cells target distant organs
 
LOS ANGELES—Most cancers kill because tumor cells spread beyond the primary site to invade other organs—and now a University of Southern California (USC) study of brain-invading breast cancer cells circulating in the blood reveals they have a molecular signature indicating specific organ preferences.
 
The findings, which appear in Cancer Discovery, help explain how tumor cells in the blood target a particular organ and may enable the development of treatments to prevent the spread of cancers, known as metastasis.
 
In this study, Min Yu, assistant professor of stem cell and regenerative medicine at the Keck School of Medicine of USC, isolated breast cancer cells from the blood of breast cancer patients with metastatic tumors. Analyzing the tumor cells in animal models, Yu’s lab identified regulator genes and proteins within the cells that apparently directed the cancer’s spread to the brain. To test this concept, human tumor cells were injected into the bloodstream of animal models.
 
As predicted, the cells migrated to the brain. Additional analysis of cells from one patient’s tumor predicted that the cells would later spread to the patient’s brain—and they did.
 
Yu also discovered that a protein on the surface of brain-targeting tumor cells helps them to breach the blood-brain barrier and lodge in brain tissue, while another protein inside the cells shield them from the brain’s immune response, enabling them to grow there.
 
 “We can imagine someday using the information carried by circulating tumor cells to improve the detection, monitoring and treatment of the spreading cancers,” Yu said. “A future therapeutic goal is to develop drugs that get rid of circulating tumor cells or target those molecular signatures to prevent the spread of cancer.”
 
Cell stiffness may indicate whether tumors will invade
 
CAMBRIDGE, Mass.—Engineers at the Massachusetts Institute of Technology (MIT) and elsewhere have tracked the evolution of individual cells within an initially benign tumor, showing how the physical properties of those cells drive the tumor to become invasive, or metastatic.
 
The team carried out experiments with a human breast cancer tumor that developed in the lab. As the tumor grew and amassed more cells over a period of about two weeks, the researchers observed that cells in the interior of the tumor were small and stiff, while the cells on the periphery were soft and more swollen. These softer, peripheral cells were more apt to stretch beyond the tumor body, forming “invasive tips” that eventually broke away to spread elsewhere.
 
The researchers found that the cells at the tumor’s edges were softer because they contained more water than those in the center. The cells in the center of a tumor are surrounded by other cells that press inward, squeezing water out of the interior cells and into those cells at the periphery, through nanometer-sized channels between them called gap junctions.
 
“You can think of the tumor like a sponge,” says Ming Guo, an assistant professor of mechanical engineering at MIT. “When they grow, they build up compressive stresses inside the tumor, and that will squeeze the water from the core out to the cells on the outside, which will slowly swell over time and become softer as well—therefore they are more able to invade.”
 
When the team treated the tumor to draw water out of peripheral cells, the cells became stiffer and less likely to form invasive tips. Conversely, when they flooded the tumor with a diluted solution, the same peripheral cells swelled and quickly formed long, branchlike tips that invaded the surrounding environment.
 
The results, which the team reports in the journal Nature Physics, point to a new route for cancer therapy, focused on changing the physical properties of cancer cells to delay or even prevent a tumor from spreading.
 
Scientists suspect that cancer cells that migrate from a main tumor are able to do so in part because of their softer, more pliable nature, enabling the cells to squeeze through the body’s labrynthine vasculature and proliferate far from the initial tumor. Past experiments have shown this soft, migratory nature in individual cancer cells, but Guo’s team is reportedly the first to explore the role of cell stiffness in a whole, developing tumor.
 
“People have looked at single cells for a long time, but organisms are multicellular, three-dimensional systems,” Guo says. “Each cell is a physical building block, and we’re interested in how each single cell is regulating its own physical properties, as the cells develop into a tissue like a tumor or an organ.”
 
The researchers used recently developed techniques to grow healthy human epithelial cells in 3D and transform them into a human breast cancer tumor in the lab. Over the next week, the researchers watched as the cells multiplied and coalesced into a benign primary tumor that comprised several hundred individual cells. Several times throughout the week, the researchers infused the growing number of cells with plastic particles.
 
They then probed each individual cell’s stiffness with optical tweezers, a technique in which researchers direct a highly focused laser beam at a cell. In this case, the team trained a laser on a plastic particle within each cell, pinning the particle in place, then applying a slight pulse in a attempt to move the particle within the cell, much like using tweezers to pick an egg shell out from the surrounding yolk.
 
Guo says the degree to which researchers can move a particle gives them an idea for the stiffness of the surrounding cell: The more resistant the particle is to being moved, the stiffer a cell must be. In this way, the researchers found that the hundreds of cells within a single benign tumor exhibit a gradient of stiffness as well as size. The interior cells were smaller and stiffer, and the further the cells were from the core, the softer and larger they became. They also became more likely to stretch out from the spherical primary tumor and form branches, or invasive tips.
 
Also as part of the work, the researchers obtained a sample of a patient’s breast cancer tumor and measured the size of every cell within the tumor sample. They observed a gradient similar to what they found in their lab-derived tumor: Cells in the tumor’s core were smaller than those closer to the periphery.
 
“We found this doesn’t just happen in a model system—it’s real,” Guo says. “This means we may be able to develop some treatment based on the physical picture, to target cell stiffness or size to see if that helps. If you make the cells stiffer, they are less likely to migrate, and that could potentially delay invasion.”
 
Perhaps one day, he says, clinicians may be able to look at a tumor and, based on the size and stiffness of cells, from the inside out, be able to say with some confidence whether a tumor will metastasize or not.
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Article derived from a story written by Jennifer Chu for the MIT News Office
 
Removing cancer’s protective barrier could boost immunotherapy treatments
 
LONDON—Scientists may have found a way to pull down the protective wall that surrounds tumors, potentially re-exposing them to the killing power of the immune system and immunotherapy treatments, according to a study part funded by Cancer Research UK and published in EBioMedicine recently.
 
Although this is early research in the lab, the findings suggest this approach could help to boost the effects of innovative cancer treatments, such as CAR-T therapy, which so far haven’t been used successfully to tackle solid tumors.
 
Dr. Francis Mussai and Dr. Carmela De Santo, who are based at the University of Birmingham, studied immune cells, called myeloid-derived suppressor cells or MDSCs, taken from the blood of 200 adults and children newly diagnosed with cancer before they had started treatment.
 
These cells send out a barrage of chemical signals that shield tumor cells from the immune system and the effects of treatment, and prevent the activation of T cells that can kill tumors.
 
When MDSCs are present in higher numbers, the outlook for patients is worse as their cancer can become resistant to treatment and is more likely to spread to other parts of the body. Researchers showed that an antibody drug that is already available for leukemia was able to destroy these immune cells, which protect the solid tumor from the immune system.
 
“Treatments that work with the immune system to kill cancer often fail because it can be difficult for our body’s defences to get access to the tumor cells,” said Dr. Francis Mussai, lead author of the study and Cancer Research UK Clinical Scientist Fellow at the University of Birmingham. “Our research indicates that giving this antibody drug alongside immunotherapies could dramatically increase the number of patients benefitting from the latest innovations in treatment.”
 
Previously, researchers in another group had found a way to break the protective layer around tumors in mice by using antibodies that attach to the MDSC cell surface, marking it for destruction by the immune system. But translating this into clinical trials has been challenging because researchers have been unable to find a drug target that is present on human MDSCs.
 
In this latest study, the team used blood samples taken from patients and showed that a protein called CD33 is present on the surface of MDSCs across a wide range of cancers.
 
By using an antibody drug called gentuzumab ozogamicin that targets CD33, which is already used to treat acute myeloid leukemia, the researchers were able to kill the MDSCs in the samples and restore the ability of T cells to attack the tumor cells.
 
The researchers also showed that active MDSCs prevented CAR-T cells from working; however, when they added the antibody drug, it boosted the activity of the CAR-T cells.
 
“This is the first time we’ve been able to effectively target the immune cells that form a barrier around solid tumors,” noted Mussai. “If this approach works in patients it could improve treatments for many different types of cancer, in both adults and children. We envision our approach will have the most impact in CAR-T therapy, which despite showing lots of promise in blood cancer, so far it’s had limited success in solid tumors.”
 
Added Dr. Emily Farthing, research information manager at Cancer Research UK: “Although this is early research, it’s increased our understanding of the way tumors interact with the immune system, and has given us a tantalizing insight into how we could make immunotherapies work for more patients in the future. But we are still a long way off in getting this treatment to patients. The next step will be to learn more about the side effects of the antibody drug, and how it works in the body.”
Roswell Park team develops new DNA-mapping tool
 
BUFFALO, N.Y.—A scientist at Roswell Park Comprehensive Cancer Center has developed what is said to be the first dedicated tool for analyzing a DNA-mapping technology known as ATAC-seq, a technique that identifies the gene “switches” responsible for cancer development and progression. Developed in collaboration with the University at Buffalo, the innovative computational method, named HMMRATAC, could vastly improve current methods of cancer detection and treatment, according to Roswell Park.
 
ATAC-seq (assay for transposase-accessible chromatin sequencing) is a relatively simple method that helps scientists identify active regions of the genome. A special enzyme called transposase is used to selectively cut and label open chromatin, and the bits of DNA that are captured can then be analyzed to reveal key information about diseases such as cancer. Although ATAC-seq has been widely used in cancer research since 2013, the massive amounts of data generated by this method are currently analyzed with algorithms initially designed for older sequencing methods, which inevitably leads to misinterpretation of the results and misses potentially important information contained in DNA fragments unique to this particular sequencing method.
 
HMMRATAC (which stands for hidden Markov modeler for ATAC-seq) is reportedly the first and only computation tool dedicated to ATAC-seq and, unlike other methods of genomic analysis, HMMRATAC is a machine learning approach that splits the DNA obtained from a single ATAC-seq dataset into accessible and inaccessible regions. The unique chromatin structure around accessible regions is then analyzed in order to predict where other genetically active areas of interest are located across the entire genome.
 
“HMMRATAC outperforms all other methods used in the field to identify open and active chromatin, because it takes advantage of the unique features of ATAC-seq to identify chromatin structure more accurately,” says Dr. Tao Liu, senior author on the study and assistant professor of oncology in the Department of Biostatistics and Bioinformatics at Roswell Park. “As HMMRATAC is a cross-platform and user-friendly algorithm dedicated to ATAC-seq, we envision it becoming the standard tool used for ATAC-seq data analysis.”
 
The software’s algorithm is built upon the idea of decomposition and integration, where many layers of complex genetic information are broken down until patterns emerge that reveal the location of the specific genes and proteins that drive various disease types, including cancer. The ultimate goal is to use this information to personalize medicine by understanding how individual variations in gene expression influence cancer development, prognosis and treatment.
 
 
Code: E121937

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