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.
