Two recent discoveries by stem cell scientists at Cedars-Sinai may help make cancer treatment more efficient and shorten the time it takes for people to recover from radiation and chemotherapy.
In the first study, published in the journal Blood, investigators discovered a protein that is expressed by blood stem cells that could aid in identifying, studying and deploying the cells for treatments.
"We show that this protein, syndecan-2, identifies primitive blood stem cells and it regulates stem cell function," said John Chute, MD, director of the Division of Hematology and Cellular Therapy at Cedars-Sinai and senior author of the study.
Blood stem cells are found in small quantities in the bone marrow and in peripheral blood—the type that travels through the heart, arteries, capillaries and veins. These stem cells are of interest to scientists because they produce all blood cells and immune cells in the body. They are used in the curative treatment of people with leukemia and lymphoma.
This approach faces a major challenge: Hematopoietic stem cells make up less than 0.01% of cells in the bone marrow and peripheral blood, and there is not yet a good way to separate them from other cells. This means that when people receive infusions of bone marrow and peripheral blood cells, they get a tiny number of stem cells that are therapeutic along with a lot of other cells that are not.
(University of Virginia Health System via EurekAlert) New guidelines for treating cancers that have spread to the brain are poised to improve care for patients and help many live longer, better lives.
The new guidelines come from an expert panel assembled by the American Society of Clinical Oncology (ASCO). The panel included a diverse range of top cancer doctors, including UVA Cancer Center’s David Schiff, MD, as well as a patient representative.
The guidelines speak to the massive advances in care for brain metastases (cancers that have spread to the brain) over the last few decades. Attempts to develop guidelines in the 1970s largely emphasized steroids and whole-brain radiation therapy, without controlled, randomized studies to guide the use of surgery and chemotherapy.
The new guidelines are far more encompassing and far more evidence-based. They will help doctors and patients make the best treatment decisions and achieve the best outcomes.
“When I started in this field 30 years ago, the average survival with brain metastases was 4 months, and most patients died from the brain disease. With improvements in therapies, fewer than one-quarter of patients die from the brain metastases, and some patients live years or are even cured,” said Schiff, a co-chair of the ASCO panel and the co-director of UVA Cancer Center’s Neuro-Oncology Center. “Equally importantly, the use of advanced localized radiation techniques and new targeted chemotherapies and immunotherapies have improved the quality of survival for most patients suffering from brain metastases.”
(EurekAlert) The detection and quantification of cancer-associated molecular biomarkers in body fluids, or liquid biopsies, prove minimally invasive in early cancer diagnostics. Researchers at the University of Illinois Urbana-Champaign have developed an approach that accelerates the detection of cancer biomarkers in samples taken at the time and place of patient care.
The study, published in ACS Nano, focused on the detection of a group of molecular biomarkers called microRNAs (miRNAs), small, single-stranded and noncoding RNAs that play important roles in gene expression and regulation. More importantly, miRNAs have been linked to certain cancer types and stages and as such, have garnered increased attention.
“Since tumor-specific mutations in miRNAs can be linked to tumor progression and metastasis, we can use miRNAs for early cancer diagnostics and therapy selection in the future,” said Congnyu Che, bioengineering graduate student in the Cunningham lab and first author of the paper. “Conventional detection methods take up to several hours for the person to get the result so our motivation was to accelerate the response time and make it shorter.”
Previously, the Cunningham group developed a technique to capture miRNA biomarkers, called Photonic Resonator Absorption Microscopy, that is capable of visualizing gold nanoparticles bound to target miRNAs. Using gold-only nanoparticles, it would take between 1-2 hours before the nanoparticles found their way to the biosensor. To accelerate the process, Che synthesized magnetic-plasmonic nanoparticles that incorporated iron materials that could then be attracted by a stationary magnet placed under the biosensor. The detection time was reduced to just one minute.
“Our approach has a one-minute response time, which means that the patient or doctor only waits for one minute before finding out the test result,” said Che.
Doctors: Cancer patients cured a decade after gene therapy
Source: AP
By LAURA UNGAR
In 2010, doctors treated Doug Olson’s leukemia with an experimental gene therapy that transformed some of his blood cells into cancer killers. More than a decade later, there’s no sign of cancer in his body.
The treatment cured Olson and a second patient, according to the University of Pennsylvania doctors, who said it was the first time the therapy had been studied for so long.
“I’m doing great right now. I’m still very active. I was running half marathons until 2018,” said Olson, 75, who lives in Pleasanton, California. “This is a cure. And they don’t use the word lightly.”
His doctors describe the two cases in a study published Wednesday in the journal Nature. They say the two examples show the treatment, called CAR-T cell therapy, can attack cancer immediately, then stay inside the body for years and evolve there to keep the disease at bay. Such so-called “living drugs” are now used by thousands around the world to treat certain blood cancers.
This 2021 photo provided by the family shows Doug Olson of Pleasanton, Calif., in Bend, Ore. In 2010, doctors treated Olson’s leukemia with an experimental gene therapy that transformed his own blood cells into cancer killers. More than a decade later, there's no sign of cancer in his body. (Family Photo via AP)
Researchers at ICMAB present a study on new nanovesicles, known as quatsomes, which have been successfully engineered to encapsulate and deliver microRNAs for the treatment of tumors. These nanovesicles are produced by a simple GMP compliant process, an unavoidable requirement for the clinical use of new drug candidates. The study, published in Small, has been highlighted in the Women in Materials Science issue of Advanced Materials.
"The beauty of these quatsomes nanovesicles is that they can be easily engineered for the delivery of a variety of nucleic acids. Importantly, they are stable at room temperature, which avoids problems associated to cold chain requirements," says ICMAB researcher Nora Ventosa at the Nanomol-Bio Group.
MicroRNAs (also known as miRNAs) are small RNA molecules that can interfere with the stability of other RNA molecules (specifically, messenger RNA). They have many potential therapeutic uses due to the central role they play in major diseases. However, these molecules are still infrequently used in patients due to their instability in the bloodstream and their poor ability to reach specific tissues. A potential strategy to improve the clinical delivery of miRNAs in the body is to encapsulate them in tiny carriers that compensate its current shortcomings, without side effects and offering other complementary functions.
Scientists at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) believe it may be possible to prevent DNA changes driven by two proteins highly active in leukemia and other cancers. They reported a new mechanistic target for drug development Jan. 21 in the journal eLife.
The proteins, called METTL-3 and METTL-14, can alter the chemical structure of DNA—the molecular vault in cells that stores a person's genetic information. This is a new understanding, said article senior author Yogesh Gupta, Ph.D., assistant professor of biochemistry at UT Health San Antonio's Greehey Children's Cancer Research Institute. For 27 years since the discovery of METTL-3 and -14, scientists believed that the proteins could only alter a separate molecule called RNA, but not DNA, he said.
RNA molecules, which float inside cells either reading out DNA instructions to make proteins or influencing this process indirectly, can form different shapes such as hairpins. Dr. Gupta, lead author; Shan Qi, a Ph.D. student in the Gupta lab; and the team observed that RNA of a certain structure like a hairpin can act as a glue that binds to METTL-3 and -14, preventing it from changing DNA's chemical structure.
As a 10-year journey comes to fruition, Medical University of South Carolina (MUSC) Hollings Cancer Center researcher John O'Bryan, Ph.D., and colleagues have demonstrated a new therapeutic way to block a protein that is frequently mutated in cancers. These proof-of-principle findings were published on Feb. 8 in Cell Reports. This work, which involves inhibiting the oncogenic protein RAS using small molecules, lays a strong foundation for the development of clinical anti-cancer therapies.
The American Cancer Society estimates that 1.9 million new cancer cases will be diagnosed this year. Based on the urgent need for more effective therapies, researchers are always on the search for elusive treatments that can affect many cancers.
O'Bryan, who is a professor in the Department of Cell and Molecular Pharmacology and Experimental Therapeutics at the Medical University of South Carolina, said, "RAS is one of the most central and critical regulators of cell proliferation, and it is also the most mutated in cancers. Mutated RAS drives the growth of tumors. This makes it an attractive therapeutic target."
University of Illinois Chicago researchers have developed a compound that may one day offer hope for pancreatic cancer treatment.
A pre-clinical study of the experimental compound shows that it more than doubles the average survival time for mice with pancreatic cancer, and that survival time was extended further when combined with immunotherapy.
Led by Ajay Rana, professor of surgery at the UIC College of Medicine and member of the University of Illinois Cancer Center, the study describes the experiments and how the compound—called XP-524—works.
XP-524 alters two proteins involved in the formation of several tumor types—bromodomain and extra-terminal motif (BET) and histone acetyltransferase EP300/CBP (EP300). The compound blocks these proteins, which helps to reactivate immune responses to the most common type of pancreatic cancer, pancreatic ductal adenocarcinoma.
Researchers develop a nanoparticle-based drug delivery system based on corn to target cancer cells https://phys.org/news/2022-02-nanoparti ... -corn.html
by Tokyo University of ScienceNishikawa from Tokyo University of Science
Nanomaterials have revolutionized the world of cancer therapy, and plant-derived nanoparticles have the added advantage of being cost-effective and easy to mass produce. Researchers from Tokyo University of Science have recently developed novel corn-derived bionanoparticles for targeting cancer cells directly, via an immune mechanism. The results are encouraging, and the technique has demonstrated efficacy in treating tumor-bearing laboratory mice. Moreover, no serious adverse effects have been reported in mice so far.
Nanoparticles, or particles whose size varies between 1 and 100 nanometers, have shown tremendous potential in many areas of science and technology, including therapeutics. However, conventional, synthetic nanoparticles are complicated and expensive to produce. Extracellular vesicles (EVs), which have emerged as an alternative option to synthetic nanoparticles, show challenges for mass production.
Another recently emerging option is that of plant-derived nanoparticles (NPs), which can be easily produced in high levels at relatively lower costs. Like EVs, these nanoparticle-based systems also contain bioactive molecules, including polyphenols (which are known antioxidants) and microRNA, and they can deliver drugs to target organs in our bodies.
After examining 398 proteins, a University of Houston College of Pharmacy researcher has found one that is an important biomarker predicting therapy outcome and a potential drug target in estrogen receptor-positive (ER+) breast cancer, which makes up approximately 80% of all breast cancers. The growth of ER+ breast cancer is stimulated by estrogen.
"We found that NPY1R, a well-known G protein-coupled receptor (GPCR) important in body weight regulation, serves as a predictor of endocrine sensitivity and of long-term outcomes in ER+ breast cancer, making it a potential drug target in estrogen receptor-positive breast cancer," said Meghana Trivedi, associate professor of pharmacy practice and translational research and pharmacology and director of clinical and translational research at the University of Houston College of Pharmacy. Her findings are published in Scientific Reports.
GPCRs represent the largest superfamily of cell-surface proteins and are highly 'druggable' targets. Nearly 30–50% of all Food and Drug Administration-approved drugs target various GPCRs and are often used to treat various chronic diseases due to their excellent safety profile. But, GPCRs have not been systematically explored as biomarkers or drug targets in breast cancer until now.
"We interrogated the expression and phosphorylation status of 398 non-sensory GPCRs using the landmark breast cancer proteogenomics and phosphoproteomic dataset from The Cancer Genome Atlas," said Trivedi. "We found NPY1R to be highly expressed in Luminal A subtype of breast cancer, which has overall favorable outcomes. However, its expression declined when the breast cancer cells developed resistance to endocrine therapy. We also reported that the inhibitory action of NPY on estradiol-stimulated growth of ER+ breast cancer cells was mediated by NPY1R. Our results demonstrated NPY1R expression as a predictor of endocrine sensitivity in ER+ breast cancer."
Killing cancer cells without affecting surrounding normal cells is the most desirable approach for targeted cancer therapy. However, it cannot be easily achieved due to the similarities in the properties between normal and cancer cells. Researchers at the IBS developed an innovative approach called CINDELA (Cancer-specific INDEL Attacker), which attacks cancer-specific mutations and causes multiple DNA double-strand breaks to specifically induce cancer cell death. It is hoped that CINDELA can become a potential approach for personalized cancer treatments in most tumors.
Diagnosis of cancer may be the worst news to patients and their families. Conventional treatment options such as radiation and chemotherapies often kill not only cancer cells but also normal cells, which results in painful side effects. Radiation and chemotherapies destroy cancer cells by producing DNA double-strand breaks in their DNA. Since both treatments target DNA in both normal and cancer cells, radiation and chemo-drugs cannot distinguish between cancer and normal cells. Thus, indiscriminate killing of healthy cells and side effects are unavoidable when using these treatments. Therefore, scientists have long sought a method to selectively target only cancer cells without affecting normal cells, which is a crucial requirement for ideal cancer therapy.
Multiple myeloma (MM) is a largely incurable cancer of plasma cells with an extremely poor prognosis. However, investigators from Japan have recently found that a common component of amino acid transporters, CD98 heavy chain, represents an effective monoclonal antibody target in treating MM.
In a study published this month in Science Translational Medicine, researchers from Osaka University have revealed a new approach that involves extensive screening of monoclonal antibody clones against primary human tumor samples. The aim was to identify cancer-specific conformational epitopes on ubiquitous proteins that cannot be identified by transcriptome or proteome analyses.
Some patients with MM show relapse in disease often due to immune-evading mutations that arise, making the cancer cells resistant to treatment. New target antigens are therefore urgently needed to develop a multi-targeted approach that can circumvent immune evasion and thereby avoid relapse of disease.
Extensive previous efforts have focused on targeting cancer-specific cell surface antigens identified by transcriptome or proteome analyses. But these efforts may have missed cancer-specific antigen epitopes formed by covalent, enzymatic modification of proteins (i.e., posttranslational modifications), such as glycosylation, or conformational changes. To widen the search for novel target antigens, Hasegawa and colleagues screened for cancer-specific monoclonal antibodies and then characterized their target-presenting antigens.
"By screening over 10,000 monoclonal antibody clones raised against MM cells, we identified R8H283, a monoclonal antibody that recognizes the CD98 heavy chain protein, which is part of an amino acid transporter," says lead author of the study Kana Hasegawa. "Despite the CD98 heavy chain being present on all cells, the antibody only bound to MM cells. This selectivity may reflect the differing glycosylation patterns between normal cells and MM cells."
Targeting a specific protein that is often overexpressed in prostate cancer can help prevent or delay the disease from spreading to other parts of the body, according to a study led by Cedars-Sinai Cancer investigators.
The research, published in the peer-reviewed journal Nature Communications, opens the possibility of using available commercial drugs, including one approved by the Food and Drug Administration for leukemia, to shut down a protein known as receptor-interacting protein kinase 2—or RIPK2. If confirmed in human clinical trials, the finding could have a major impact on the treatment of men with advanced prostate cancer.
"About 90% of cancer deaths are caused by the recurrence of metastatic cancer, which occurs when cancer spreads to other organs," said Wei Yang, Ph.D., associate professor of Surgery and Biomedical Sciences. "So, if we can prevent the occurrence of metastatic cancer, we can substantially extend the lives and improve the quality of life for men with this disease."
To better understand the genetic drivers of disease development and potential treatment targets, the Cedars-Sinai team examined the molecular profiles of cancer tissue in men with advanced prostate cancer. The investigators discovered that RIPK2 was amplified in about 65% of lethal prostate cancers, which kill approximately 34,000 U.S. men each year.
Patients receiving radiotherapy to treat high-risk prostate cancer also benefit from androgen deprivation therapy. The ideal duration of treatment may be roughly two years if receiving external beam radiation and one year if receiving external beam radiation with a brachytherapy boost, according to a study published in JAMA Oncology.
The use of androgen deprivation therapy (ADT) combined with radiation therapy improves cancer outcomes, but comes with significant side effects including effects on the cardiovascular system, mood, lowered libido and loss of muscle mass. This forces clinicians and patients to weight benefits versus costs for use and duration of treatment with ADT, according to Ashley Ross, MD, Ph.D., associate professor of Urology and a co-author of the study.
"Determining the optimal balance for length of therapy is paramount," said Ross, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
In recent years, great advances have been made in the development of new successful immunotherapies to treat cancer. CAR T-cell therapy and antibody treatments are two types of targeted immunotherapies that have revolutionized areas of cancer care. However, there are still significant challenges in the identification of cancer cell surface proteins as targets for immunotherapies. A research group at Lund University in Sweden is well on the way and have now published their findings in PNAS.
Immunotherapies have revolutionized the treatment of cancer and, in some cases, are able to cure patients with advanced disease. Immunotherapies with CAR T-cells and antibodies share a focus on specific target proteins expressed on the surface of tumor cells, known as cell surface tumor antigens.
"The great challenge is that the structure of cell surface tumor antigens differs between patients and between primary tumors and metastases. There is a great need both for new strategies and for high precision identification of accessible, treatable cell surface tumor antigens at a personalized level. We have worked for many years to establish new methods that provide knowledge about antigens on the surface of cancer cells as a target for immunotherapies," says Mattias Belting, professor of clinical oncology at Lund University and consultant at Skåne University Hospital.
Many melanoma patients are treated with drugs called BRAF or MEK inhibitors that specifically target the mutant proteins created in cancerous tumors. These inhibitors can block the tumors' ability to grow and spread.
According to Ann Richmond, Ingram Professor of Cancer Research and professor of pharmacology and dermatology, while these inhibitors are shown to be rapidly effective and to increase survival rates, most patients eventually experience relapse. To help solve this problem, Richmond and other researchers at Vanderbilt School of Medicine Basic Sciences used spatial imaging analysis of tissues. These imaging techniques allowed researchers to investigate the properties of the tumors and immune cells in patients before and after developing resistance to the BRAF and MEK inhibitors.
When observing post-treatment resistant tumors, Chi Yan, research assistant professor of pharmacology and first author of the study, found significantly more melanoma cells with biomarker SOX10 present, indicating that these cells may be treatment-resistant. SOX10 plays a role in the differentiation of precancerous cells into cancerous melanocytes, which are skin cells associated with skin pigmentation. Presence of SOX10 is thought to create an environment that blocks the immune system from being able to regulate tumor growth, and loss of expression of SOX10 is associated with reduced tumor formation.
For years, researchers at Huntsman Cancer Institute at the University of Utah (U of U) have honed a process of developing breast cancer models using tumors donated by breast cancer patients, which they then implant into mice as a way to study the tumor's behavior.
Now, the research team reports a new, more efficient way to grow these tumors. In addition, they outline a process to test potential drugs to help prioritize clinical therapy choices based on unique tumor characteristics.
The study, published this week in the journal Nature Cancer, creates a way for researchers to narrow the number of drugs that might be effective in each tumor based on its unique characteristics and its behavior in the laboratory models of the cancer. Using this resource, the researchers uncovered experimental and Food and Drug Administration-approved drugs with high efficacy against the models. They extended this work to personalize therapy for a patient with metastatic breast cancer, which resulted in a complete response for the patient and a progression-free survival period more than three times longer than her previous therapies.
"We were able to utilize the data to prioritize therapy options for a patient," says Alana Welm, Ph.D., co-lead author, breast cancer researcher at Huntsman Cancer Institute, and professor of oncological sciences at the U of U. "While this therapy was unfortunately not curative, it led to regression of the patient's tumor and a longer survival period."
One of the most promising avenues in treating cancer is to restore our immune system's ability to recognize and attack cancerous cells. A team of University of Chicago chemists and biologists developed a tiny device that can locate tumor cells and force them to reveal themselves to patrolling immune cells. In tests with mice, this resulted in tumor regression.
"When it comes to drug delivery, the problem, as molecular biologist Inder Verma put it, is delivery, delivery, and delivery," explained Yamuna Krishnan, a professor in the Department of Chemistry and an author of the study. "These DNA nanodevices now make drug delivery hyperspecific, allowing us to think of ways to treat cancer without killing the cell that the therapeutic is delivered to."
The focus of these nanodevices is a particular type of cell known as tumor-associated macrophages, or TAMs. Macrophages are a type of immune cell that normally is supposed to recognize and remove microbes, cellular debris, and other foreign substances from cells; but if something goes wrong with them, they can become a key part of cancerous tumors. TAMs can comprise up to 50% of tumor mass in triple-negative breast cancer.
However, "despite the high abundance of TAMs in solid tumors, mechanisms underlying their impact on tumor development and therapeutic strategies to target them are incompletely understood," said study co-author Lev Becker, associate professor in the Ben May Department for Cancer Research.
Researchers at the University of Michigan Rogel Cancer Center found that a cytokine, a category of protein that acts as messengers in the body, and a fatty acid can work together to trigger a type of cell death previously defined by studies with synthetic molecules.
The study, published in Cancer Cell, looked at cell cultures and in vivo mouse experiments to see how the release of a T-cell cytokine called interferon gamma combined with arachidonic acid, a fatty acid, leads to a type of cell death called ferroptosis via targeting the enzyme ACSL4. Ferroptosis has been found to occur in tumor cells and play a role in cancer immunity. Understanding how ferroptosis occurs could open pathways to make immunotherapy treatments more effective.
"Targeting ACSL4 may help in understanding and expanding possible immunotherapy options," said Weiping Zou, M.D., Ph.D., director the Center of Excellence for Cancer Immunology and Immunotherapy and lead researcher on this study.
In order to better treat patients diagnosed with acute myeloid leukemia (AML), the pathological processes and also existing subtypes of the disease must be better understood. With the help of proteome and genome analysis, researchers at the Max Planck Institute (MPI) of Biochemistry in Martinsried, together with cooperation partners from the University Hospital in Frankfurt am Main, have discovered a new subtype. This subgroup contains elevated levels of mitochondrial proteins and thus has altered mitochondrial metabolism. These so-called mito-AML cells can be combated more effectively in laboratory experiments with the help of inhibitors against mitochondrial respiration than with conventional chemotherapeutic agents. The study was published in Cancer Cell.
Identification of molecular AML subtypes
Acute myeloid leukemia (AML) is an aggressive cancer originating from blood cells. When immature blood cells in the bone marrow acquire certain aberrations in their genome they become malignant and overgrow the bone marrow, the place where normally blood cells are produced. As a consequence, normal blood cells are suppressed by the leukemia cells and this leads to infections, bleeding and ultimately death of patients. Most patients diagnosed with AML undergo chemotherapy.
