Cancer News and Discussions

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A new approach to therapy-resistant tumors targets a specific cell-death pathway
https://medicalxpress.com/news/2022-05- ... death.html
by InsideOutBio

In a paper appearing in Nature today, an international group of scientists report a new way to kill hard-to-treat cancers. These tumors resist current immunotherapies, including those using Nobel Prize-winning checkpoint-blocking antibodies.

The approach exploits Z-DNA. Rather than twisting to the right like B-DNA, Z-DNA has a left-handed twist. One role for Z-DNA is to regulate the immune response to viruses. The response involves AADR1 and ZBP1, two proteins that specifically recognize Z-DNA. They do so through a Zα domain that binds to the Z-DNA structure with high affinity.

The Zα domain was originally discovered by Dr. Alan Herbert of InsideOutBio, a communicating author on the paper. The ADAR1 Zα domain turns off the autoimmune response, while the other ZBP1 Zα turns on pathways that kill virally infected cells, as previously shown by Dr. Sid Balachandran, the other communicating author on the paper. The interactions between ADAR1 and ZBP1 determine whether a tumor cell lives or dies.
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Novel macrophage-mediated mechanism promotes peritoneal metastasis of ovarian cancer
https://phys.org/news/2022-05-macrophag ... arian.html
by The University of Hong Kong
A research team at the School of Biological Sciences, the University of Hong Kong (HKU), has revealed novel cellular and molecular interactions between cancer cells and tumor-associated macrophages that promote peritoneal metastasis of ovarian cancer. These findings provide important insights into the therapeutic strategy of ovarian cancer and are now published in Advanced Science, an interdisciplinary open-access journal.

Ovarian cancer is the leading cause of deaths among all gynecological cancers. More than 70% of patients are diagnosed at an advanced stage with metastatic diseases. Peritoneal metastasis is very difficult to treat due to tumor heterogeneity and the dynamic interactions of cancer cells with the tumor microenvironment. The lack of suitable experimental models has been one significant obstacle to study the cellular and molecular mechanisms of this critical process, and the distinct interactions among different cancer cell subclones and tumor microenvironment are largely unknown using traditional bulk measurement.

Key findings: In metastatic ovarian cancer cells, Wnt/b-catenin signaling upregulates the expression of metadherin, which communicates with macrophages through CEACAM1, a carcinoembryonic antigen expressed by macrophages, suggesting that blockade of macrophage-tumor communications (by inhibiting either metadherin or CEACAM1) could greatly reduce peritoneal metastasis.
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Working to stop the spread of breast cancer
https://medicalxpress.com/news/2022-05- ... ancer.html
by Matt Davenport, Michigan State University
Michigan State researchers are revealing the molecular workings of how a certain form of metastatic breast cancer spreads to other parts of the body. In doing so, they're creating new opportunities to spot and contain what is called triple negative breast cancer.

"We focused on triple negative breast cancer, or TNBC, because it occurs proportionally more often in younger patients and has worse clinical outcomes," said Sophia Lunt, an associate professor in the College of Natural Science at MSU.

"The vast majority of TNBC-related deaths are due to metastasis, the spread of cancer cells from the primary tumor to other sites in the body," Lunt said. "Metastatic breast cancer is not curable, and available treatments aim to only slow disease progression."

Since joining MSU in 2015, Lunt's research has focused on understanding the role of metabolism—which nutrients and compounds cancer cells use and how—in metastasis. She and her team are now reporting results from their work on triple negative breast cancer, so named because its tumor cells test negative for three types of proteins used in diagnoses.
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T cells found to require rest and maintenance

by Bill Hathaway, Yale University
https://medicalxpress.com/news/2022-05- ... nance.html
T cells, biology textbooks teach us, are the soldiers of the immune system, constantly on the ready to respond to a variety of threats, from viruses to tumors. However, without rest and maintenance T cells can die and leave their hosts more susceptible to pathogens, Yale scientists report May 27 in the journal Science.

"We may have to change how we teach T cell biology," said Lieping Chen, the United Technologies Corporation Professor in Cancer Research at Yale, professor of immunobiology, of dermatology, and of medicine and senior author of the study.

Until pathogens are detected, T cells remain in a quiescent state. However, the molecular mechanisms that keep T cells inactive were previously unknown.

In the new study, Yale researchers show that a protein known as CD8a—which is found in a subset of T cells called CD8 cells—is crucial to keeping the cells in this dormant state. When scientists deleted this protein in mice, the protective CD8 cells were unable to enter a quiescent state and died, leaving the host vulnerable to infections.
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Ultrasound-guided microbubbles boost immunotherapy efficacy
https://phys.org/news/2022-05-ultrasoun ... icacy.html
by University of Texas M. D. Anderson Cancer Center

Researchers at The University of Texas MD Anderson Cancer Center have developed an ultrasound-guided cancer immunotherapy platform that generates systemic antitumor immunity and improves the therapeutic efficacy of immune checkpoint blockade. The findings from the preclinical study were published today in Nature Nanotechnology.

As the first-of-its-kind platform, the Microbubble-assisted UltraSound-guided Immunotherapy of Cancer (MUSIC) approach employs nanocomplexes combined with microbubbles to effectively deliver cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), an immunotransmitter involved in anticancer immunity, into antigen-presenting cells (APCs). Inside the APCs, the microbubbles release cGAMP to activate the GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which stimulates type I interferon responses that are essential for priming tumor-specific T cells.

In the preclinical study, the MUSIC strategy demonstrated a complete tumor eradication rate of 60% when administered as monotherapy in breast cancer models. When combined with an anti-PD-1 antibody, MUSIC significantly improved antitumor responses with minimal toxicity effects, including enhanced primary tumor control and decreased systemic disease progression. In addition, the combination therapy demonstrated superior survival benefit, with a 76% increase in median survival compared to either therapy alone.
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New Study Shows Racial Disparities in Guideline-Concordant Care for Early-Onset Colorectal Cancer Patients
May 31, 2022

Entire article less brief description of the American Cancer Society and disclaimer:
(EurekAlert) In a new large national study led by researchers at the American Cancer Society (ACS), Black patients diagnosed with early-onset colorectal cancer received worse and less timely care than their white counterparts. Differences in health insurance coverage type, a modifiable factor, according to the findings, were the largest identified contributor to the racial disparities. The study results will be presented at this year’s annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, June 3-7.

In the study, led by Dr. Leticia Nogueira, senior principal scientist, health services research at the American Cancer Society, more than 147,000 non-Hispanic Black and white individuals aged 20-49 years newly diagnosed with colorectal cancer during 2004-2019 were selected from the National Cancer Database. Patients who received all care recommended by the National Comprehensive Cancer Network (staging, surgery, lymph node evaluation, chemotherapy, and radiotherapy) for which they were eligible according to cancer subsite and clinical and pathological TNM stage were considered guideline-concordant. Demographic characteristics (age and sex), comorbidities, and health insurance coverage type were added sequentially to a series of multivariable models to estimate the contribution to racial disparities in receipt of guideline-concordant care. Racial disparities in time from diagnosis date (among rectal cancer patients eligible for neoadjuvant chemotherapy) and surgery date (among colon cancer patients eligible for adjuvant chemotherapy) to date of chemotherapy initiation was evaluated using restricted mean time to treatment.

Of the 84,728 colon and 62,483 rectal cancer patients included in the study, 20.8% and 14.5% were Black, respectively. Black patients were 18 and 36% less likely to receive guideline-concordant care than white patients diagnosed with colon and rectal cancer, respectively. Demographic characteristics and comorbidities combined explained less than 5% of the disparity, while health insurance coverage type explained 28.6% and 19.4% of the disparity among colon and rectal cancer patients, respectively. Restricted mean time to chemotherapy was statistically significantly longer among Black than white patients for colon (54.0 vs. 48.7 days) and rectal cancers (49.6 vs. 40.9 days), respectively.

Study authors stress improved access to care could help mitigate disparities in cancer outcomes.
Source: https://www.eurekalert.org/news-releases/954404
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Immune therapy targets cells that cause leukemia relapse
https://medicalxpress.com/news/2022-06- ... lapse.html
by Weill Cornell Medical College

Genetically engineered immune cells successfully target the specific cancer cells that may be responsible for relapse of acute myeloid leukemia (AML), a type of blood cancer, and proved effective in animal models of the disease, according to a preclinical study by investigators at Weill Cornell Medicine. The new cell therapy, now being tested in phase 1 clinical trials, may ultimately help patients with AML to remain cancer-free.

In the study, published April 28 in Nature Communications, the researchers used an approach in which immune cells known as T cells are directed to produce proteins called chimeric antigen receptors, or CARs, that enable the T cells to recognize specific markers on cancer cells. In this case, the CAR is a receptor that binds to the CD123 molecule on leukemia stem cells, enabling the T cells to seek out and attack the cancer cells.

"Leukemia stem cells are a subset of leukemic cells that are resistant to standard chemotherapy drugs and can cause disease relapse," said co–senior author Dr. Monica L. Guzman, associate professor of pharmacology in medicine in the Division of Hematology & Medical Oncology and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. "CD123 is a marker found on leukemia stem cells, and my laboratory has been working on designing mouse models to test new CD123-targeted anti-leukemia therapies."
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Promising results for chemo-immunotherapy combination against pancreatic cancer
https://medicalxpress.com/news/2022-06- ... ancer.html
by University of Pennsylvania

A combination of chemotherapy with an immunotherapy meant to unleash the anticancer capacity of the immune system was effective against one of the hardest targets in cancer care, pancreatic cancer, in a national, randomized clinical trial led by researchers at the Perelman School of Medicine at the University of Pennsylvania, and sponsored by the Parker Institute for Cancer Immunotherapy.

The results of the small but promising trial were announced today in a presentation at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, and simultaneously published in Nature Medicine.

The researchers found that in 34 patients with advanced pancreatic cancer randomized to receive the immunotherapy nivolumab with two chemotherapy drugs, nab-paclitaxel and gemcitabine, had a one-year survival rate of 57.7 percent, significantly greater than the historical average of 35 percent with chemotherapy alone. The findings also included the identification of immune system biomarkers associated with better outcomes. A second treatment of the immunotherapy sotigalimab with chemotherapy also appeared more effective in a subgroup of patients, identified with a different set of biomarkers.

"This study suggests there is benefit of combining immunotherapy and chemotherapy in patients with advanced pancreatic cancer and there may be ways to fine tune treatment choices based on the 'immune health' of the patient," said Robert H. Vonderheide, MD, DPhil, the John H. Glick Abramson Cancer Center Professor and director of the Abramson Cancer Center at Penn. "We now hope to evaluate these potential biomarkers in further trials to see if they'll enable us reliably to identify patients who will respond best to this and other combination therapies. The most promising biomarkers were measured by a blood test of the immune system, not genetic sequencing, which opens the door for a new approach in precision oncology."
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Researchers use nanotechnology to destroy and prevent relapse of solid tumor cancers
https://phys.org/news/2022-06-nanotechn ... ncers.html
by National University of Singapore
As people across the globe look forward to longer life expectancies, malignant cancers continue to pose threats to human health. The exploration and development of immunotherapy aims to seek new breakthroughs for the treatment of solid tumors.

The successful establishment of anti-tumor immunity requires the activation, expansion and differentiation of antigen-specific lymphocytes. This process largely depends on specific interactions between various T cells and antigen-presenting cells (APCs) in the body. However, existing tumor vaccines, such as neoantigen vaccines and various vector vaccines, all rely on random interactions with APCs in the body. Furthermore, inappropriate interactions may lead to the silencing of other immune responses.

Although immune checkpoint-based immunotherapy has been shown to have great potential, only a small proportion of patients fully respond to this therapy, and the relevant molecular mechanisms need to be further explored. This delivery method is however complex and inefficient.

In a breakthrough development, a team of scientists led by Narat Muzayyin Chair Professor Chen Xiaoyuan from the NUS Yong Loo Lin School of Medicine and Professor Liu Gang from Xiamen University has formulated a novel vaccine which showed high efficacy in the treatment of solid tumors, achieving complete clearance of solid tumors and inducing long-lasting immune memory. This prevents the relapse of tumor growth that the patient originally presented with and provides immunity against similar tumor types. This was proven through the application of this vaccine on melanoma tumor models. Their results are published in Nature Nanotechnology.
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