A combination of two drugs showed promise in treating relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 (FLT3) gene, according to a Northwestern Medicine study published in the Journal of Clinical Oncology .
The combination of venetoclax, an inhibitor of BCL2, and gilteritinib, an FLT3 inhibitor, has the potential to improve outcomes and allow patients to utilize oral medications instead of treatments that must be delivered in the hospital, according to senior author Jessica Altman, MD, professor of Medicine in the Division of Hematology and Oncology.
According to a previous study published in the New England Journal of Medicine, survival of patients with refractory or relapsed AML is improved when using gilteritinib, compared to chemotherapy. Gilteritinib targets the FLT3 mutation. Typically, relapsed or refractory AML has a median overall survival of four to seven months with standard chemotherapy approaches.
In the current phase II trial, investigators studied the efficacy of adding venetoclax to gilteritinib. Investigators treated patients with relapsed or refractory AML with venetoclax and gilteritinib daily. Of the 61 patients enrolled, 56 of them had disease with the FLT3 mutation and 64% of those with the mutation had received prior FLT3 inhibitor therapy.
The study found a molecular response, defined as FLT3-ITD VAF less than or equal to 10 in 60% of participants with FLT3 -ITD who attained a modified complete remission, which was higher than with gilteritinib alone.
While chemotherapy drugs can be lifesaving, they don't work for all patients or for all cancers. But a team of UTM researchers is looking at new ways to use special types of light to target cancer cells resistant to current drug therapy—in an approach that might be easier on some patients than traditional chemotherapy.
Photodynamic therapy—the use of precisely targeted light, usually from a laser, that activates or "turns on" a drug to kill cells—has been used mostly to treat skin cancers, since it's easier to deliver light to the outside of the body. But light doesn't travel very far through body tissues. So how to safely get the light to cancers that are deeper inside, such as in the pancreas or breast? And how to recognize which cancers will respond to the cell-killing drugs and which will be resistant? The challenge is to get the light as close as possible to red light. Of all the colors in the visible light spectrum, red has the longest wavelength, which enables it to penetrate tissue, but also the lowest energy, which minimizes harm to healthy cells.
Karishma Kailass, a Ph.D. candidate in the department of chemical and physical sciences, found that using an approach called two-photon light, where two tiny particles of light hit at exactly the same time, achieved this result. It doubled the wavelength, halved the energy and, together with a special cancer-killing molecule that's activated only by light, successfully destroyed cancer cells that would otherwise have been resistant to conventional chemotherapy.
As a part of our immune defenses, cytotoxic T cells—or killer T cells—seek out and destroy cells that are infected or cancerous. This process is essential for the body's defense against diseases.
These specialized immune cells are armed with lytic granules containing two key components for immune attack: perforin (proteins that punch holes in the target cells) and granzymes (which gain access via these holes and ultimately kill disease-causing cells).
T cells snuggle up to targeted diseased cells and form an intimate junction between the two, called the "cytotoxic immunological synapse."
A research team at UNSW Sydney's EMBL Australia Node in Single Molecule Science in the School of Biomedical Sciences has found that mechanical forces generated by T cells influence how effectively perforin can punch through tumor cell membranes. In a paper published today in Developmental Cell, they describe the cell interactions and the integration of forces at both the front and rear of the cell.
Women diagnosed with early-stage breast cancer often can choose to have a lumpectomy, which removes only cancerous tissue and a thin margin of surrounding healthy cells instead of the entire breast. Current cancer guidelines for most women under 65 recommend following lumpectomy with radiation therapy, which targets stray cancer cells that might otherwise cause breast cancer to recur or spread to other parts of the body.
A new study presented at the 2022 annual meeting of the American Society of Clinical Oncology could eventually expand an option for skipping radiation to some women as young as 55. However, limitations in necessary testing could hinder the approach from becoming widespread, according to a Harvard expert.
A lower risk for breast cancer recurrence
Landmark 2004 research, augmented by later studies, helped cancer experts develop guidelines defining which women with early-stage breast cancer could safely omit radiation after lumpectomy.
Generally, this option is offered to women 65 or older who have small tumors with nonaggressive cells that haven't spread to the lymph nodes. Medically, this is described as a T1N0, grade 1-2 tumor. The tumors must be estrogen receptor-positive, meaning that the hormone estrogen helps fuel their growth. They also must have an adequate margin of normal tissue surrounding the tumor cut away to ensure all the cancer has been removed. Women who decide to omit radiation instead receive medication known as endocrine therapy for five years. This stops cancer cells from using hormones like estrogen to grow and spread.
Engineers at the Georgia Institute of Technology and Stanford University have created a small, autonomous device with a stretchable/flexible sensor that can be adhered to the skin to measure the changing size of tumors below. The non-invasive, battery-operated device is sensitive to one-hundredth of a millimeter (10 micrometers) and can beam results to a smartphone app wirelessly in real-time with the press of a button.
In practical terms, the researchers say, their device—dubbed FAST for "Flexible Autonomous Sensor measuring Tumors"—represents a wholly new, fast, inexpensive, hands-free, and accurate way to test the efficacy of cancer drugs. On a grander scale, it could lead to promising new directions in cancer treatment.
Each year researchers test thousands of potential cancer drugs on mice with subcutaneous tumors. Few make it to human patients, and the process for finding new therapies is slow because technologies for measuring tumor regression from drug treatment take weeks to read out a response. The inherent biological variation of tumors, the shortcomings of existing measuring approaches, and the relatively small sample sizes make drug screenings difficult and labor-intensive.
Just as bacteria, viruses and fungi develop strategies to outsmart antimicrobial medications, cancer cells can become resistant to chemotherapy. And among tumors, those associated with triple negative breast cancer and ovarian tumors can develop a powerful form of resistance.
In an intriguing line of research, a multi-center team of U.S. researchers has found that epigenetic signatures in breast and ovarian cancers may ultimately guide physicians' treatment decisions for a subset of patients whose cancers are notoriously capable of thwarting chemo.
By pinpointing which molecular signatures correlate with optimum treatment response, oncologists can be better informed when designing treatment regimens for cancers with reputations for aggressive drug resistance.
Reporting in Science Translational Medicine, cancer biologists at Jackson Laboratory for Genomic Medicine in Farmington, Connecticut, spell out why triple negative breast cancer—TNBC—and ovarian carcinoma are especially difficult to treat. For one thing, loss of BRCA1 or BRCA2 gene activity is common in TNBC and ovarian cancer the scientists underscored, and has a potent bearing on prognosis. However, the type of alteration involving the genes can result in different responses to treatment, the researchers said.
Alveolar rhabdomyosarcoma is a type of rare pediatric tumor. For more than 40 years there have not been any new developments regarding treatment. Research led by Prof. Dr. Anton Henssen at Charité University Berlin has now identified a new therapeutic option, using a drug that is currently under investigation for other types of cancer. The group observed that alveolar rhabdomyosarcoma cancer cells have high levels of DNA damage and are more dependent on the repair processes than non-cancer cells. This drug blocks the repair of DNA and forces cells to die, thus offering a new option for treating these patients.
Rhabdomyosarcomas are tumors that grow in the muscle tissue, predominantly in children and adolescents. Even though they are rare, they represent the second most common solid tumor in childhood. Alveolar rhabdomyosarcoma is a type of rhabdomyosarcoma characterized by a chromosome translocation that creates a new protein fusion called PAX3-FOXO1. Alveolar rhabdomyosarcomas are the more aggressive version, with an overall survival rate of 30% after five years. In Europe, it is estimated that around 500 new rhabdomyosarcoma cases are diagnosed every year, of which 100 are alveolar rhabdomyosarcoma. Despite many advances in cancer therapeutics, rhabdomyosarcoma treatment has not changed in the last four decades, therefore new and more effective treatments are needed.
One of the challenges in treating alveolar rhabdomyosarcoma is the lack of druggable factors present in the tumor. Besides the PAX3-FOXO1 fusion, alveolar rhabdomyosarcomas do not present many recurrent genetic mutations, thus limiting our ability to use drugs specific for this tumor. Simultaneously, cancer cells frequently present higher DNA damage, which allows the acquisition of new mutations. The damaged DNA needs to be repaired before the cells can divide to ensure that the integrity of the genome is maintained. In recent years, many drugs have been developed to block the repair of the DNA, with promising results in multiple cancer types.
Over the last decade, immune checkpoint blockers, or ICBs, have revolutionized treatment for various advanced cancers, including melanoma, the most aggressive skin cancer that was considered largely incurable not long ago. However, three-fourths of advanced-melanoma patients are resistant to ICBs.
Now, in a report published in Nature Communications, researchers reveal a potential target—using the clinically approved drug ruxolitinib—to suppress ICB-resistant melanomas.
"Since ruxolitinib is clinically approved and being tested in patients with advanced solid tumors, non-small-cell lung cancer and triple-negative breast cancer, our study justifies further testing of ruxolitinib in patients with advanced melanoma that are resistant to ICBs," said Lewis Zhichang Shi, M.D., Ph.D., an associate professor in the University of Alabama at Birmingham Department of Radiation Oncology.
Shi notes that ruxolitinib will likely need to be combined with other therapeutic modalities to achieve a long-term cure.
For half a dozen years, it was known that tumor loss of interferon-gamma signaling was a major mechanism of resistance against two ICB drugs, anti-CTLA-4 and anti-PD-1. However, ways to overcome this resistance remained elusive.
This loss of interferon-gamma signaling in human melanomas is caused by dysregulation of genes in the interferon-gamma signaling pathway. However, in mouse models the knockdown mutations failed to show how a loss of interferon-gamma signaling in tumor cells modulated the activity of tumor-infiltrating T cells, or TILs, because those models still contain some interferon-gamma signaling. TIL immune cells are vital for cancer control because they are able to detect and destroy tumors. However, in a countermove, cancers learn to evade this destruction by upping immune checkpoint proteins on the surface of their cells, and these surface proteins send an "off" signal to TILs.
One approach to treating cancer is photodynamic therapy using photo-uncaging systems, in which light is used to activate a cancer-fighting agent in situ at the tumor. However, suitable agents must be stable under visible light, have an anti-tumor effect in low-oxygen environments, and have the ability to be activated by low-energy tissue-penetrative red light—a combination of properties that is difficult to achieve. Now, a team from The Institute of Industrial Science at The University of Tokyo has developed a new platform that uses, for the first time, organorhodium(III) phthalocyanine complexes to achieve this combination of traits.
Conventional photodynamic techniques depend on the formation of reactive oxygen species to destroy tumor cells, but many tumors contain environments that lack oxygen. Photo-uncaging systems, where the agent is administered in an inactive form and then activated, or "uncaged", in the location of the tumor, address this issue. They uncage alkyl radicals, which are known to be capable of inducing cell death both with and without the presence of oxygen. Alkyl radicals are converted into terminal aldehydes in the presence of oxygen, and these terminal aldehydes can also induce cell death. The team used molecules called "organorhodium(III) phthalocyanine (Pc) complexes" to develop, for the first time, a novel platform for photo-uncaging therapy.
"The organorhodium(III) phthalocyanine (Pc) complexes we developed are highly stable under ambient light during the processes of synthesis, purification, and measurement, but can be activated by a laser that gives out nanosecond pulses of red light," explains lead author Kei Murata. These nanosecond-pulsing lasers (pulsing for a billionth of a second) are relatively easy for medical staff to handle.
DNA damage is one of the foundational causes of cancer. But researchers have now found that deliberately causing DNA damage—by delivering additional treatments like radiotherapy—could improve the effectiveness of immunotherapy for some people with kidney cancer.
Immunotherapy can work by stimulating people's own immune systems to fight cancer more effectively. In people with kidney cancer who also have a mutation in the PBRM1 gene, damaging DNA before immunotherapy could further activate the immune system.
The study, led by scientists at The Institute of Cancer Research, London, and published in Genes and Development, sheds light on the role of PBRM1, and suggests that kidney cancer patients with mutations in the gene could benefit from a combined treatment of radiotherapy and immunotherapy.
Findings suggest that the PBRM1 gene is crucial in preventing cells from dividing when they contain damaged DNA. Researchers found that mutations in PBRM1 disrupt this process and allow the cells with damaged DNA to multiply, triggering inflammatory signals that are thought to enhance the patient's immune response against cancer.
Scientists are still trying to understand why many breast cancer survivors experience troubling cognitive problems for years after treatment. Inflammation is one possible culprit. A new long-term study of older breast cancer survivors published today in the Journal of Clinical Oncology and co-led by UCLA researchers adds important evidence to that potential link.
Higher levels of an inflammatory marker known as C-reactive protein (CRP) were related to older breast cancer survivors reporting cognitive problems in the new study.
"Blood tests for CRP are used routinely in the clinic to determine risk of heart disease. Our study suggests this common test for inflammation might also be an indicator of risk for cognitive problems reported by breast cancer survivors," said study lead author Judith Carroll, an associate professor of psychiatry and biobehavioral sciences and faculty member of the Cousins Center for Psychoneuroimmunology at UCLA.
Researchers at UNC Lineberger Comprehensive Cancer Center have found a possible way to overcome barriers that block effective anti-cancer immune responses, thereby opening the potential for more effective immunotherapies in people.
The findings are published in Nature.
An unfavorable immune environment immediately surrounding a tumor cell is a major obstacle in using immunotherapy to treat many solid tumors, especially pancreatic and breast cancer, as the suppressive environment can block immune responses that could be helpful in attacking a tumor. One protein, the STimulator of INterferon Genes (STING), has the promise of powerfully provoking multiple parts of the immune system and breaking established barriers.
"Although activating the immune system to control malignant tumors has revolutionized cancer treatment, a sizable portion of patients do not respond to immunotherapy treatments. However, new drugs that target STING have been a high priority for pharmaceutical development yet clinical trials have revealed significant tumor resistance to STING-directed drugs," said UNC Lineberger's Jenny PY Ting, Ph.D., the William R. Kenan Professor of Genetics and professor of microbiology and immunology at the UNC School of Medicine.
"Clinically, to improve the effectiveness of STING-targeted drugs, we need to more deeply understand how these drugs influence different immune cells in the tumor because the beneficial effects of STING on immunity may be outweighed by its unintended immune-suppressive effect," said Ting, the paper's co-corresponding author and director of the Center for Translational Immunology at UNC.
A team of scientists and doctors from the KK Women's and Children's Hospital (KKH), Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine) and the Institute for Health Innovation and Technology has discovered a novel, noninvasive method to predict and reduce the relapse of childhood cancers.
The most common form of solid tumor affecting children is neuroblastoma. It is known to be the cause of a disproportionate number of childhood cancer deaths. The majority of relapsed patients would have a very low chance of survival despite being given the best care.
"The bone marrow is the site where majority of neuroblastoma relapses occur. This discovery provides a simplified method of assessing cancer spread. The current method of sampling bone marrow can be complex, painful and costly. This is particularly daunting for young patients and their families," explained Dr. Amos Loh, Senior Consultant at the Department of Pediatric Surgery, Deputy Chair of the Division of Surgery, and Chair of the Pediatric Brain and Solid Tumor Program, KK Women's and Children's Hospital.
"Where current methods may show patients as cancer-free at the end of treatment, our novel approach may detect 'leftover' disease not identified by current means. This could one day save patients' lives through appropriate early interventions to prevent relapse," added Dr. Loh.
Skoltech researchers and their colleagues from the Pushchino Scientific Center for Biological Research of RAS and Lomonosov Moscow State University discovered a never-before-seen substance with anti-tumor properties in the extract of the fungus Aspergillus cavernicola. The study was published in the Journal of Agricultural and Food Chemistry.
Cis-cavernamine, a pigment present in the A. cavernicola extract, was found to turn into another compound that the researchers dubbed monasnicotinic acid (MNA). They used human prostate and bladder cancer cells to check whether MNA has anti-tumor activity and discovered that it hinders the growth and migration of cancer cells by blocking the AKT/mTOR signaling pathways.
"MNA's anti-tumor effect is promising, although not strong enough yet. We plan to enhance this capability by tweaking the molecule's structure and have already applied for an RSF grant to continue this research. While modified versions of MNA stand a good chance of evolving into effective cancer drugs, cis-cavernamine can be used by the food industry right away," said Tatiana Antipova, lead author and senior research scientist at the Skryabin Institute of Biochemistry and Physiology of Microorganisms of RAS in Pushchino.
Cancer cells use an unusual mechanism to migrate into new tissue and form metastases there. The same process probably also keeps some immune cells on their toes. This is the result of a recent study led by the University of Bonn.
According to the study, certain structures, the centrioles, increase in number. This makes it easier for them to maintain their direction and thus migrate more quickly to the lymph nodes, where they activate other immune cells. The results have now been published in the Journal of Cell Biology.
Like the police, the immune system relies on division of labor. First of all, there are the dendritic cells. They search the tissue around the clock for traces of suspicious intruders, called antigens. If they are successful, they rush to the lymphatic vessels and from there to the draining lymph nodes. There they present their findings to a powerful search team, the T cells. These endogenous troops now know which enemy to fight.
This attack must take place before the invaders cause major damage or multiply too much. It is therefore important that dendritic cells migrate as quickly as possible to the briefing in the lymph node. "We have discovered a mechanism that helps them doing this," explains Prof. Dr. Eva Kiermaier from the LIMES Institute (Life and Medical Sciences) at the University of Bonn. "To do so, they form more of certain structures called centrosomes. These help them maintain their direction for longer and thus reach the lymphatic vessels more quickly."
Breast cancers that emerge within five years of giving birth are more likely to spread and become deadly. Additionally, a new study shows that recent childbirth alone is an independent risk factor for breast cancer progression.
The findings suggest that current clinical guidelines, which don't factor in postpartum status, are less able to accurately predict the risk of cancer recurrence and guide optimal treatment strategies in young patients.
"This has profound implications for prognosis," said senior author Pepper Schedin, Ph.D., professor of cell, developmental and cancer biology in the OHSU School of Medicine and OHSU Knight Cancer Institute. "A postpartum diagnosis can move women who appear to have good prognosis into a high-risk category."
A paper describing the research published today in JAMA Network Open. OHSU Knight Cancer Institute scientists Zhenzhen Zhang, Ph.D., M.P.H., and Solange Bassale, M.S., are co-first authors.
The researchers were able to confirm the link between pregnancy and breast cancer outcomes using the extensive Utah Population Database, in collaboration with Ken Smith, Ph.D., co-senior author of the paper and a distinguished professor of family studies and population science at the University of Utah's Huntsman Cancer Institute. The database combines statewide birth and death records, Utah Cancer Registry data, and patient records from statewide inpatient and ambulatory records.
Researchers at Mount Sinai's Tisch Cancer Institute have identified a new gene that is essential to colon cancer growth and found that inflammation in the external environment around the tumor can contribute to the growth of tumor cells. The scientists reported these findings in Nature Communications.
This is the first time that scientists have discovered that the environment around a colon cancer tumor can program what is known as a "super enhancer," a complex area of DNA with a high concentration of transcriptional machinery that controls whether a cell is malignant.
This super enhancer—the largest 1-2% of all enhancers in the cell—regulates the gene PDZK1IP1, which was previously not identified as a cancer gene. Once researchers deleted PDZK1IP1, colon cancer growth slowed down, suggesting that PDZK1IP1 and its super enhancer could be targets for anti-cancer therapies.
"In the United States, colon cancer is the third most prevalent and second most deadly cancer," said the study's first author Royce Zhou, an MD/Ph.D. student at the Icahn School of Medicine at Mount Sinai. "This cancer is reliant on surgery for treatment, and immunotherapies that have revolutionized the treatment of advanced cancer have only worked for a small subset of colon cancer patients. That's why there's a great need for novel target identification."
Pancreatic cancer often lurks as a silent disease. With no known symptoms, it can progress undetected and spread to other organs.
According to the National Cancer Institute, more than 60,000 Americans will be diagnosed with pancreatic cancer this year, and only about 1 in 10 of those diagnosed will survive the next five years. The disease ranks as the third leading cause of cancer deaths in the U.S. because it is rarely detected in the early stages when treatment options are most effective.
Pancreatic cancer's stealth-like nature has the attention of University of Florida scientists, who have discovered a way to reverse a key cellular process involved in its progression. Their study, "Pharmacological Inhibition and Reversal of Pancreatic Acinar Ductal Metaplasia," was published in the journal Cell Death Discovery.
The UF researchers identified two small molecules that inhibit precancerous cell progression. The molecules also reversed a process known as acinar ductal metaplasia, or ADM, which precedes pancreatic cancer.
A Ludwig Cancer Research study has developed a strategy to non-invasively track immune cells known as macrophages within brain and breast tumors in living mice. Cancers often recruit and reprogram these tumor-associated macrophages, or TAMs, to support their own growth and confer resistance to therapies. Led by Ludwig Lausanne's Johanna Joyce and Davide Croci and their colleague at the Lausanne University Hospital, Ruud B. van Heeswijk, the study appears in the current issue of Science Translational Medicine and is featured on the cover of the journal.
"Macrophage monitoring has the potential to significantly improve the therapeutic management of a variety of cancers," said Joyce. "Brain malignancies, among the deadliest primary cancers and metastases, especially depend on the presence of macrophages and the targeting of these immune cells may represent a key strategy for their treatment."
Endothelial cells—the cells that line blood vessels—grown alongside leukemia cells become corrupted and rescue the cancer cells from many chemotherapy drugs, a study by Weill Cornell Medicine investigators found.
A growing body of evidence suggests that genetic mutations are not enough to cause cancer; tumor cells also need the right environment to grow. The new study, published in Blood on Aug. 18, found that endothelial cells can protect T-cell acute lymphoblastic leukemia (T-ALL) cells, which cause an aggressive type of blood cancer, from chemotherapy drugs that would otherwise kill the cancer cells. The discovery and the platform they used could improve the way scientists find and test new drugs for the condition.
"We have identified endothelial cells as a new player in T-ALL," said co-senior author Dr. Giorgio Inghirami, professor of pathology and laboratory medicine and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. "Our platform may lead to more effective drug discovery programs and better clinical trials."