Tag Archives: #tumors

Study Sheds Light on Mechanism of Liposome Accumulation in Tumors (Medicine)

CU Cancer Center researcher says results could impact how we diagnose, monitor, and treat tumors with liposomes.

Dmitri Simberg, PhD, an associate professor in the Department of Pharmaceutical Sciences in the Skaggs School of Pharmacy and a CU Cancer Center member, has released the results of a new study of the effectiveness of different types of fluorescent labels used to monitor the accumulation of liposomes in tumors.

The new study, titled “Liposomal Extravasation and Accumulation in Tumors as Studied by Fluorescence Microscopy and Imaging Depend on the Fluorescent Label,” was published on July 1, 2021, in the prestigious journal of the American Chemical Society, ACS Nano.

Liposomes, a type of nanoparticle, are tiny, fat-soluble vesicles (small, fluid-filled sacs) made from lipids, or fats. They are mainly used to deliver cancer-fighting drugs to tumors, since liposomes are not water soluble and can protect some drugs against breaking down in the body.

Comparing fluorescent labels on liposomes for enhanced tumor imaging

In the new study, Simberg and his collaborator Irina Balyasnikova, PhD, from the Department of Neurological Surgery at Northwestern University, wanted to determine whether the accumulation of liposomes in tumors depends on the type of fluorescent label used.

“It’s very important for the liposome to get out to the tumor blood vessels in order to reach tumor cells and other cells in the microenvironment. So, we asked whether liposome accumulation in tumors depends on which fluorescent label you use,” Simberg explains.

“It’s the first finding of its kind, showing that different lipids have different abilities to accumulate in tumors.” – Dmitri Simberg, PhD

To accomplish this, they made liposomes containing two different classes of fluorescent lipids in the same liposome: indocarbocyanine lipids (ICLs) and fluorescent phospholipids (FPLs). Then they injected them into breast cancer and brain cancer mouse models and used fluorescent microscopy and imaging to compare how much of each label accumulated in the tumors.

Both types of fluorescent labels initially accumulated in the tumor blood vessels. However, over time, the ICLs continued to accumulate, spreading over a significantly larger tumor area and reaching immune and tumor cells, while the FPLs quickly degraded and disappeared from the tumors.

“What we found is that even when injected into the same liposome, ICLs showed remarkable accumulation and extravasation (infiltrating the tumors), while FPLs, though a very similar type of fluorescent group, did not show much extravasation and essentially disappeared,” Simberg says.

“It’s the first finding of its kind, showing that different lipids have different abilities to accumulate in tumors,” he adds.

Results could lead to improved liposomal drug delivery

The team’s findings open the door to improved cancer drug-delivery systems.

“There is a lot of interest in using lipids as a kind of shuttle to get the drugs into tumors,” Simberg says. “It’s an exciting opportunity to enhance drug delivery in different tumors, particularly glioma, a type of brain tumor that’s especially difficult to penetrate.”

Although a lot of labs make liposomes and nanoparticles, there has not been much mechanistic understanding of exactly how they interact with tumors and how they cross the endothelial barrier. “We’re really advocating for studies that offer a deeper mechanistic understanding of how these drug-delivery systems work,” Simberg says.

Simberg says the most impactful part of this paper and his lab’s ongoing research is its focus on understanding the mechanics and structure of lipids that determine the efficiency of tumor accumulation.

The next step in the team’s research will be studies to try additional fluorescent lipids. “In this paper, we compared two lipid types, but we want to expand on that to build a large library of fluorescent lipids and use the most efficient ones to deliver anticancer drugs, eventually testing them for therapeutic efficacy in glioma and other tumor models,” Simberg says.


Provided by Anschutz

Cellular Signatures Of Kidney Tumors Discovered (Medicine)

This method of identification holds promise as a tool for diagnosing patients with rare cancers

The origins of seven types of kidney cancer, including several rare subtypes, have been identified by researchers at the Wellcome Sanger Institute, Great Ormond Street Hospital (GOSH), the Princess Máxima Center for Pediatric Oncology and Oncode Institute. The findings confirm that these cancers have their origin in specific forms of developmental cells present in the maturing fetus.

The study, published today (23 June) in Nature Communications, used computational methods to analyse existing datasets and pinpoint the ‘cellular signals’ given off by different cancers as they emerge. This method holds promise as a tool for diagnosing patients with rare cancers – in the study, one patient’s cryptic kidney cancer was identified as a Wilms-like tumour by looking at its cellular signals.

All cancers are derived from normal cells that have started to multiply uncontrollably. By comparing patterns of gene expression in cancer and normal cells, it is possible to learn about aspects of each tumour’s origin and behaviour. This type of analysis has been made possible by the advent of single-cell mRNA sequencing, a high-resolution technology that can identify different cell types present in a tissue according to the genes expressed by individual cells.

Previous studies have used these techniques to compare normal and diseased tissue in some of the most common kidney cancers, but to conduct single-cell sequencing on many hundreds of tumours would not be achievable.

In this study, researchers at the Wellcome Sanger Institute and their collaborators turned to computational techniques to mine Human Cell Atlas (HCA) reference data* and databases of tumour gene expression. They assessed mRNA signals in 1,300 childhood and adult renal tumours, spanning seven different tumour types, in order to investigate the origins of these cancers**.

The results confirmed that these childhood cancers are developmental in origin, occurring after errors in a particular developmental cell type’s journey to maturity. In contrast, adult kidney cancers emerged from mature cell types and do not revert to a developmental pattern of gene expression in the vast majority of cases.

Each cancer type was also found to exhibit unique ‘cellular signals’, or patterns of gene expression, that could be used to classify them in future.

“It has long been assumed that childhood tumours have ‘fetal’ origins. Now we can replace that loose definition with a precise, quantitative measurement of the cellular signals that different tumour types exhibit. Our analysis also refutes the theory that adult tumours revert to a developmental state, unless they are a highly lethal subtype of adult kidney cancer.”

Dr Matthew Young,first author of the study from the Wellcome Sanger Institute

The study sheds light on the behaviour and origins of some kidney tumour subtypes whose rarity would have made it difficult to examine otherwise. These were congenital mesoblastic nephroma, clear cell sarcoma of the kidney, malignant rhabdoid tumour of the kidney, and chromophobe renal cell carcinoma.

The method pioneered in the study also helped to classify one patient’s tumour, which clinicians had been unable to diagnose fully.

“Sometimes it is not possible to fully diagnose childhood kidney cancers via the usual methods, which can impact our ability to adopt the best course of treatment. One of the samples used in this study was from a child with one of these undiagnosed tumours. But by analysing the genes expressed by the tumour cells, we were able to recognise it as Wilms’ tumour. My hope is that this approach can be used in such cases in future.”

— Dr Karin Straathof,a senior author of the study from Great Ormond Street Hospital

In recent studies, researchers have identified the origins of individual childhood cancers, such as neuroblastoma, using mRNA single-cell sequencing on small numbers of tumours. Here, computational analysis of existing data has been used to determine the origin of a larger groups of childhood cancers.

“Not only does this computational approach using existing datasets validate previous results on the origins of childhood kidney cancers, it provides a new way of expanding this research to much larger numbers of tumours and rare cancer types. I believe that the success of this approach could act as a blueprint for investigating the behaviour and origins of the entire spectrum of human cancer.”

Dr Sam Behjati,a senior author of the study from the Wellcome Sanger Institute

More information

*Single-cell RNA sequencing (scRNAseq), used to assess which genes are active in individual cells, can be used on millions of cells at once and generates vast amounts of data. The Human Cell Atlas project uses such techniques to uncover and characterise all of the cell types present in an organism or population. https://www.sanger.ac.uk/news_item/human-kidney-map-charts-our-growing-immune-defence/

** Bulk transcriptomes are an aggregate of gene expression for both tumour and normal cells. The types of cancer analysed in the study were:

  • Congenital mesoblastic nephroma (CMN)
  • Nephroblastoma (also known as Wilms tumour)
  • Clear cell sarcoma of the kidney (CCSK)
  • Malignant rhabdoid tumour of the kidney (MRTK)
  • Clear cell renal cell carcinoma (ccRCC)
  • Papilliary renal cell carcinoma (pRCC), subtypes type 1 and type 2
  • Chromophobe renal cell carcinoma (ChRCC), subtype “Metabolically divergent ChRCC”

Publication:

Matthew D. Young, Thomas D. Mitchell and Lars Custers et al. (2021). Single cell derived mRNA signals across human kidney tumors. Nature Communications. DOI: https://doi.org/10.1038/s41467-021-23949-5

Funding:

This work was funded by Wellcome, the St. Baldrick’s Foundation, Great Ormond Street Hospital Children’s Charity (J.C.A.), Children Cancer-free Foundation (KiKa), and Great Ormond Street Hospital Biomedical Research Centre.

Featured image credit: Kenny Roberts, Bayraktar Lab


Provided by Wellcome Sanger Institute

Replicating Patients Tumours To Test Different Treatments (Medicine)

UNIGE Researchers have developed in vitro tumour models that incorporate components of the tumour and elements of the patient’s immune system to test the effectiveness of treatments.

Every tumour is different, every patient is different. So how do we know which treatment will work best for the patient and eradicate the cancer? In order to offer a personalised treatment that best suits the case being treated, a team of scientists led by the University of Geneva (UNIGE), Switzerland, had already developed a spheroidal reproduction of tumours that integrates the tumour cells, but also their microenvironment. However, the immune system had not yet been taken into account, even though it can either be strengthened or destroyed by the treatment given to the patient. Today, the Geneva team has succeeded in integrating two types of immune cells that come directly from the patient into the spheroidal structure, making it possible to test the various possible treatments and select the most effective. These results can be read in the journal Cancers.

In order to test cancer treatments, scientists use 2D cultures of cancer cells. However, these are only an artificial system, as they do not represent the 3D tumour in all its complexity. This is why the team of Patrycja Nowak-Sliwinska, professor at the Section of Pharmaceutical Sciences of the Faculty of Science of the UNIGE, has developed a spheroidal structure that reproduces the microenvironment of the tumour. “The idea is to create a 3D structure from the cells of the tumour, while also integrating the fibroblasts –  cells that make up the mass of the tumour –  and the endothelial cells, which allow the tumour to feed and be vascularised.” This method, which has since been used by the University Hospitals of Geneva (HUG), allows us to get closer to the tumour as it is present in the patient’s body. “However, an important factor was still missing: the cells of the immune system”, explains the Geneva researcher.


The critical role of the immune system in the fight against cancer

The immune system is the primary fighter against tumours and it reacts differently depending on the treatment prescribed to the patient: its effectiveness can either be increased or decreased. Today, the Geneva team, in collaboration with the universities of Lausanne and Amsterdam, has succeeded in integrating two types of immune cells into its spheroidal structure: macrophages and T lymphocytes. “This technological advance makes it possible to test the effects of a treatment not only on the tumour, but also on the immune system!”, enthuses Magdalena Rausch, researcher at the UNIGE’s Section of Pharmaceutical Sciences and first author of the study. To do this, the scientists first take cells from the patient’s tumour to recreate it in vitro in the form of a spheroidal structure, and then they isolate the immune cells and inject them into the 3D structure. “Once this step has been completed, which takes 24 hours, we can test the various possible treatments for this cancer on our reproduction of the tumour and study which one will be most suitable for the patient, taking into account the effects on the tumour cells, but also on the immune system”, explains Patrycja Nowak-Sliwinska.

This technique, which is relatively inexpensive and fast, would make it possible to propose a personalised treatment for each patient, while offering an effective alternative to several animal experimentations. “This platform opens up many possibilities for testing drug combinations, taking into account the different types of cancer, their mutations and the immune reactions specific to each person treated”, concludes Patrycja Nowak-Sliwinska.

Featured image: The spheroid includes cancer cells, endothelial cells, fibroblasts, monocytes and human T cells. Fluorescently labelled immune cells (green, monocytes; red, T cells) can infiltrate the preformed spheroid within 12 hours. Scale bar = 100 µm. © Magdalena Rausch


Reference: Rausch, Magdalena; Blanc, Léa; De Souza Silva, Olga; Dormond, Olivier; Griffioen, Arjan W.; Nowak-Sliwinska, Patrycja. 2021. “Characterization of Renal Cell Carcinoma Heterotypic 3D Co-Cultures with Immune Cell Subsets” Cancers 13, no. 11: 2551. https://doi.org/10.3390/cancers13112551


Provided by University of Geneve

New Nanoparticle Design Paves Way For Improved Detection of Tumors (Medicine)

Nano-sized particles have been engineered in a new way to improve detection of tumors within the body and in biopsy tissue, a KTH research team reports. The advance could enable identifying early stage tumors with lower doses of radiation.

In order to enhance visual contrast of living tissues, state-of-the-art imaging relies on agents such as fluorescent dyes and biomolecules. Advances in nanoparticle research have expanded the array of promising contrast agents for more targeted diagnostics, and now a research team from KTH Royal Institute of Technology has raised the bar further yet. They are combining optical and X-ray fluorescence contrast agents into a single enhancer for both modes.

Muhammet Toprak, Professor of Materials Chemistry at KTH, says the synthesis of contrast agents introduces a new dimension in the field of X-ray bio-imaging. The research was reported in the American Chemical Society journal, ACS Nano.

“This unique design of nanoparticles paves the way for in vivo tumor diagnostics, using X-ray fluorescence computed tomography (XFCT),” Toprak says.

He says the new “core-shell nanoparticles” may have a role to play in the development of theranostics, a portmanteau for therapy and diagnostics, in which for example single drug-loaded particles could both detect and treat malignant tissues.

Shell structure

The core-shell contrast agent gets its name from its architecture: it consists of a core combination of nanoparticles with previously-established potential in X-ray fluorescence imaging, such as ruthenium and molybdenum (IV) oxide. This core is encased in a shell comprised of silica and Cy5.5, a near-infrared fluorescence-emitting dye for optical imaging techniques such as optical microscopy and spectroscopy.

Toprak says that encapsulating the Cy5.5 dye within the silica shell improves the agent’s brightness and extends its photo-stability—enabling the dual optical/X-Ray imaging approach. In addition, silica provides the benefit of tempering the toxic effects of the core nanoparticles.

Improving the odds of detection

Tests with laboratory mice have shown that the XFCT contrast agents enable location of early stage tumors of only a few millimetres in size.

Toprak says the technology opens the possibility to identify early stage tumors in living tissue. That’s because the presence of multiple contrast agents increases the odds that diseased areas will show up in scans, even as the distribution of the nanoparticles becomes obscured by their interaction with proteins or other biological molecules.

“Nanoparticles of different size, originating from the same material, don’t appear to be distributed in the blood in the same concentrations,” Toprak says. “That’s because when they come into contact with your body, they’re quickly wrapped in various biological molecules—which gives them a new identity.”

A multitude of contrast agents for XFCT would enable studying the biodistribution of nanoparticles in-vivo using low-dose X-rays, he says. That would allow identifying the best size and surface chemistry of the nanoparticles for the desired targeting and imaging of the diseased region.

In addition to Toprak, co-authors to the study were Giovanni M. Saladino, Carmen Vogt, Yuyang Li, Kian Shaker, Bertha Brodin, Martin Svenda and Hans M. Hertz. The project was funded by Knut and Alice Wallenberg’s Foundation, Grant number KAW2016.0057.

Featured image: A lab image shows the detection of the newly-developed nanoparticle contrast agents inside a mouse cell with optical fluorescence (in red). The cell nucleus and plasma membrane are depicted in blue and green, respectively. (Photo: Giovanni Marco Saladino)


Reference: “Optical and X-ray Fluorescent Nanoparticles for Dual Mode Bioimaging,” ACS Nano, 10.1021/acsnano.0c10127


Provided by KTH

Blood Test Detects Childhood Tumors Based On Their Epigenetic Profiles (Medicine)

A new study exploits the characteristic epigenetic signatures of childhood tumors to detect, classify and monitor the disease. The scientists analyzed short fragments of tumor DNA that are circulating in the blood. These “liquid biopsy” analyses exploit the unique epigenetic landscape of bone tumors and do not depend on any genetic alterations, which are rare in childhood cancers. This approach promises to improve the personalized diagnostics and, possibly, future therapies of childhood tumors such as Ewing sarcoma. The study has been published in Nature Communications.

A study led by scientists from St. Anna Children’s Cancer Research Institute (St. Anna CCRI) in collaboration with CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences provides an innovative method for “liquid biopsy” analysis of childhood tumors. This method exploits the fragmentation patterns of the small DNA fragments that tumors leak into the blood stream, which reflect the unique epigenetic signature of many childhood cancers. Focusing on Ewing sarcoma, a bone tumor of children and young adults with unmet clinical need, the team led by Eleni Tomazou, PhD, St. Anna CCRI, demonstrates the method’s utility for tumor classification and monitoring, which permits close surveillance of cancer therapy without highly invasive tumor biopsies.

In tumors, cancer cells constantly divide, with some of the cancer cells dying in the process. These cells often release their DNA into the blood stream, where it circulates and can be analyzed using genomic methods such as high-throughput DNA sequencing. Such “so-termed liquid biopsy” analyses provide a minimally invasive alternative to conventional tumor biopsies that often require surgery, holding great promise for personalized therapies. For example, it becomes possible to check frequently for molecular changes in the tumor. However, the use of liquid biopsy for childhood cancers has so far been hampered by the fact that many childhood tumors have few genetic alterations that are detectable in DNA isolated from blood plasma.

Exploiting tumor-specific epigenetic profiles

Cell-free DNA from dying tumor cells circulates in the blood in the form of small fragments. Their size is neither random nor determined solely by the DNA sequence. Rather, it reflects how the DNA is packaged inside the cancer cells, and it is influenced by the chromatin (i.e., complex of DNA, protein and RNA) structure and epigenetic profiles of these cells. This is very relevant because epigenetic patterns – sometimes referred to as the “second code” of the genome – are characteristically different for different cell types in the human body. Epigenetic mechanisms lead to changes in gene function that are not based on changes in the DNA sequence but are passed on to daughter cells. The analysis of cell-free DNA fragmentation patterns provides a unique opportunity to learn about the epigenetic regulation inside the tumor without having to surgically remove tumor cells or even know whether and where in the body a tumor exists.

“We previously identified unique epigenetic signatures of Ewing sarcoma. We reasoned that these characteristic epigenetic signatures should be preserved in the fragmentation patterns of tumor-derived DNA circulating in the blood. This would provide us with a much-needed marker for early diagnosis and tumor classification using the liquid biopsy concept”, explains Dr. Tomazou, Principal Investigator of the Epigenome-based precision medicine group at St. Anna CCRI.

Machine learning increases sensitivity

The new study benchmarks various metrics for analyzing cell-free DNA fragmentation, and it introduces the LIQUORICE algorithm for detecting circulating tumor DNA based on cancer-specific chromatin signatures. The scientists used machine-learning classifiers to distinguish between patients with cancer and healthy individuals, and between different types of pediatric sarcomas. “By feeding these machine learning algorithms with our extensive whole genome sequencing data of tumor-derived DNA in the blood stream, the analysis becomes highly sensitive and in many instances outperforms conventional genetic analyses”, says Dr. Tomazou.

When asked about potential applications, she explains: “Our assay works well, we are very excited. However, further validation will be needed before it can become part of routine clinical diagnostics.” According to the scientists, their approach could be used for minimally invasive diagnosis and, but also as a prognostic marker, monitoring which patient responds to therapy. Additionally, it might serve as a predictive marker during neoadjuvant therapy (i.e., chemotherapy before surgery), potentially enabling dose adjustments according to treatment response. “Right now, most patients receive very high doses of chemotherapy, while some patients may be cured already with a less severe therapy, which would reduce their risk of getting other cancers later in life. There is a real medical need for adaptive clinical trials and personalized treatment of bone tumors in children.”

Extracting tumor epigenetics from blood © CCRI

International scientific collaboration

This study was led by St. Anna CCRI in collaboration with CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Medical University of Vienna, collaborating with multiple institutions in Austria, Germany, Norway, and France.

About epigenetics

Epigenetics is the link between genes and their environment. It co-coordinates gene regulation, by determining which genes are active or inactive at specific time points. Epigenetic mechanisms lead to changes in gene function that are not based on changes in the DNA sequence – for example through mutation – but are passed on to daughter cells. Since childhood cancers often harbor few genetic alterations, their epigenetic patterns are promising markers for non-invasive diagnostics using liquid biopsy.

Publication:

Multimodal analysis of cell-free DNA whole genome sequencing for pediatric cancers with low mutational burden
Peter Peneder*, Adrian M Stütz*, Didier Surdez, Manuela Krumbholz, Sabine Semper, Mathieu Chicard, Nathan C Sheffield, Gaelle Pierron, Eve Lapouble, Marcus Tötzl, Bekir Erguner, Daniele Barreca, Andre F Rendeiro, Abbas Agaimy, Heidrun Boztug, Gernot Engstler, Michael Dworzak, Marie Bernkopf, Sabine Taschner-Mandl, Inge M Ambros, Ola Myklebost, Perrine Marec-Bérard, Susan Ann Burchill, Bernadette Brennan, Sandra J Strauss, Jeremy Whelan, Gudrun Schleiermacher, Christiane Schaefer, Uta Dirksen, Caroline Hutter, Kjetil Boye, Peter F Ambros, Olivier Delattre, Markus Metzler, Christoph Bock#, Eleni M Tomazou#

*Shared first authors
#Corresponding authors

Nature Communications, May 28 2021. Doi: 10.1038/s41467-021-23445-w.
https://doi.org/10.1038/s41467-021-23445-w.

Funding:
This study was funded by the Austrian National Bank’s Jubilaumsfonds (OeNB), the Austrian Science Fund
(FWF), the Vienna Science and Technology Fund (WWTF) and a charitable donation from Kapsch Group.

Featured image: Peter Peneder, MSc, Adrian Stütz, PhD, and Eleni Tomazou, PhD, develop a liquid biopsy analysis based on tumor epigenetics. © CCRI


Provided by CCRI

Targeting Abnormal Cell Metabolism Shows Promise For Treating Pediatric Brain Tumors (Medicine)

Two experimental drug approaches that target vulnerabilities in cancer cell metabolism may extend survival and enhance the effectiveness of standard chemotherapies for a highly aggressive type of pediatric brain cancer.

The findings were reported by Johns Hopkins Kimmel Cancer Center researchers in two published studies.

Medulloblastoma is the most common malignant pediatric brain tumor. A subset of patients with tumors known as Group 3 MYC-amplified medulloblastoma have an overall survival rate of less than 25%. In these patients, the cancer-promoting MYC oncogene drives cancer cell growth by altering cancer cell metabolism. Cancer cells use energy in ways that are different from normal cells, so they are potentially vulnerable to therapies that target the abnormal metabolic pathways downstream of MYC. 

In the first study, published March 22 in the Journal of Neuropathology and Experimental Neurology, pediatric oncologist and senior author Eric Raabe, M.D., Ph.D., associate professor of oncology at the Johns Hopkins University School of Medicine, focused on the metabolism altering drug DON (6-diazo-5-oxo-L-norleucine). DON is a naturally occurring compound studied in adult and pediatric cancer clinical trials since the 1980s, but it was never systematically tested against MYC-driven brain tumors.

Although DON was safe in children in early cancer clinical trials, it is not currently clinically available.

The research team, led by Barbara Slusher, Ph.D., M.A.S., director of Johns Hopkins Drug Discovery and professor of neurology at the Johns Hopkins University School of Medicine, modified DON to increase its ability to cross the blood-brain barrier, creating a DON prodrug, JHU395. In a prodrug, the chemistry is changed so that the drug is activated only in cancer cells.

“The promise of DON prodrugs is to develop a treatment that wouldn’t hurt normal cells but could be released preferentially in brain cancer cells,” says Raabe.

In one set of experiments, investigators treated human high-MYC medulloblastoma cell lines with JHU395 and with DON. They found the prodrug effectively suppressed growth and killed the cancer cells at lower concentrations compared to DON alone.

Next, mice bearing implanted human medulloblastoma tumors were treated with JHU395. The researchers found the treatment led to selective killing of the MYC-driven cancer cells, while normal brain cells were spared. Furthermore, JHU395 treatment significantly extended survival. Treated mice lived nearly twice as long as mice given placebo.

“JHU395 is equally effective as DON at a lower dose because it has better penetration of the brain cancer cells,” Raabe says. “Coming up with a new therapy with potentially reduced side effects means we can combine drugs for better patient survival, which is what this is all about.”

In a second study, published online Feb. 8 in Cancer Letters, Raabe and colleagues at three other cancer research institutions targeted the mammalian rapamycin complexes involved in cell metabolism. The protein mTOR signals cancer cells to grow, invade healthy tissue and resist therapy. 

Previous research showed that, in addition to high MYC expression, aggressive pediatric medulloblastoma tumors have high-level mTOR expression, pointing investigators toward mTOR inhibitors as having possible therapeutic value. A bioinformatics drug screen identified TAK228 (also known as sapanisertib), a brain-penetrating mTORC1/2 kinase inhibitor as a potentially effective agent for children, Raabe says.

Researchers found that TAK228 inhibited mTORC1/2, suppressed tumor cell growth up to 75% and effectively killed MYC-driven human medulloblastoma cancer cells.

Next, investigators focused on measuring the abnormal metabolism of MYC-driven medulloblastoma. In cancer, elevated glutathione is one means by which tumor cells become resistant to chemotherapy. Glutathione specifically allows cells to block the effect of chemotherapy drugs containing platinum, such as cisplatin and carboplatin. These platinum-containing drugs are some of the major components of medulloblastoma therapy. In human medulloblastoma tumors grown in mice, Raabe and colleagues found that the tumor cells have more glutathione than normal brain cells. Using the excess glutathione may be one way these cancer cells resist chemotherapy.

The researchers found that the TAK228 mTOR inhibitor disrupted and decreased glutathione synthesis in cancer cells. When they treated mice that had high-MYC medulloblastoma brain tumors with a combination of TAK228 and carboplatin, the combination effectively killed tumor cells and extended survival more than either drug used alone. Mice treated with combination therapy lived nearly twice as long as control mice. Of the combination-treated mice, 20% were considered very long survivors, living nearly 80 days after the start of the experiment, while all control mice died from their tumor within 25 days.

“By targeting the mTOR pathway, TAK228 overcame a key resistance mechanism that cancer cells have to traditional chemotherapy,” Raabe says. “These MYC-driven cancers make a lot of glutathione — they’re growing so fast they need a lot of it. TAK228 reduces the amount they can make, and that makes them vulnerable to the chemotherapy.”

“This is valuable pre-clinical data for future trials in children of combination mTOR inhibitor with traditional chemotherapy, which could ultimately change outcomes for children who will be diagnosed with MYC-driven medulloblastoma,” he adds.

Co-authors of the Journal of Neuropathology and Experimental Neurology study are Khoa Pham, Micah Maxwell, Heather Sweeney, Jesse Alt, Rana Rais, Charles Eberhart and Barbara Slusher.

The work was supported by the National Institutes of Health’s National Institute of Neurological Disorders and Stroke (1R01NS103927) and National Cancer Institute (R01 R01CA229451), the Spencer Grace Foundation, the Ace for the Cure Foundation, the Giant Food Pediatric Cancer Research Fund and a National Cancer Institute core grant to the Sidney Kimmel Comprehensive Cancer Center.

Other researchers participating in the Cancer Letters study are Rachael Maynard, Brad Poore, Allison Hanaford, Khoa Pham, Madison James, Jesse Alt, Youngran Park, Barbara Slusher and Charles Eberhart from Johns Hopkins, Pablo Tamayo and Jill Mesirov from the University of California San Diego, and Tenley Archer and Scott Pomeroy from the Broad Institute of the Massachusetts Institute of Technology, Harvard University and the Harvard Medical School.

Funding was provided by Alex’s Lemonade Stand Foundation for Childhood Cancer, the Spencer Grace Foundation, the Ace for the Cure Foundation, the Giant Food Pediatric Cancer Research Fund, the National Institutes of Health (U24CA220341, U01CA217885, U24CA194107, U54CA209891 and U01 CA184898) and a National Cancer Institute support grant to the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

Featured image: High-power microscope view showing human MYC-amplified medulloblastoma ( large, pale blue cells at bottom) growing in the mouse cerebellum. Normal brain is shown at top (pink colored connections between brain cells and small, dark blue brain cells). The tumor cells are pressing into and disrupting the normal brain © Khoa Pham, M.D.


References: (1) Maynard RE, Poore B, Hanaford AR, Pham K, James M, Alt J, Park Y, Slusher BS, Tamayo P, Mesirov J, Archer TC, Pomeroy SL, Eberhart CG, Raabe EH. TORC1/2 kinase inhibition depletes glutathione and synergizes with carboplatin to suppress the growth of MYC-driven medulloblastoma. Cancer Lett. 2021 Apr 28;504:137-145. doi: 10.1016/j.canlet.2021.02.001. (2) Khoa Pham, MD, Micah J Maxwell, MD, PhD, Heather Sweeney, Jesse Alt, BS, Rana Rais, PhD, Charles G Eberhart, MD, PhD, Barbara S Slusher, PhD, Eric H Raabe, MD, PhD, Novel Glutamine Antagonist JHU395 Suppresses MYC-Driven Medulloblastoma Growth and Induces Apoptosis, Journal of Neuropathology & Experimental Neurology, Volume 80, Issue 4, April 2021, Pages 336–344, https://doi.org/10.1093/jnen/nlab018


Provided by Johns Hopkins Medicine

Cells From the Centre Of Tumours Most Likely to Spread Around the Body (Medicine)

A study led by UCL researchers has discovered that cells from different parts of kidney tumours behave differently and, surprisingly, cells within the centre of a tumour are the most aggressive and have the highest chance of spreading around the body.

Cancers can spread to other parts of the body, with cells taking hold as secondary tumours which make the disease much harder to treat. Understanding the mechanics of this spread, a process called metastasis, could lead to new treatments that block this migration. 

In this multidisciplinary study published in Nature Ecology and Evolution, scientists led by Dr Kevin Litchfield at UCL Cancer Institute, with Dr Samra Turajlic, Professor Charles Swanton, and Dr Paul Bates at the Francis Crick Institute, analysed 756 cancer biopsy samples from different regions within tumours from the TRACERx Renal study.

The researchers found that cells at the centre of tumours have a less stable genome and a higher potential to spread to secondary sites around the body. By contrast cells at the tumour edge had lower rates of metastasis, as well as lower rates of growth and genetic damage.

Co-lead author Dr Litchfield, Group leader at UCL Cancer Institute, said: “Cancer cells in the central zone of the tumour face harsh environmental conditions, as there’s a lack of blood supply and oxygen. They have to adapt to survive, which makes them stronger and more aggressive. This also means they are more likely to successfully evolve into cells that can disseminate and take hold in distant organs.”

The results highlight a need to pay close attention to the tumour centre to understand how cancer spreads and to find the cancer cells of greatest threat to the patient. It also shows the importance of developing treatments that target the unique environmental conditions found within the tumour core, in order to successfully eliminate the most aggressive tumour cells. 

The scientists also looked at how genetically different populations of cancer cells grow within a tumour. Using a unique map building tool to reconstruct the growth of tumour cells, they found that, while most tumours follow a pattern where populations of cells grow in the local area – like a plant growing up and outwards – two cases demonstrated a “jumping” pattern where cells took hold in a new region of the tumour by seemingly ‘jumping’ over other populations of tumour cells.

The researchers are now planning to reconstruct 3D tumour maps, which will provide an even clearer visualisation of the spatial patterns within tumours. 

Dr Turajlic, head of the Crick’s Cancer Dynamics Laboratory, Consultant Medical Oncologist at the Royal Marsden NHS Foundation Trust, and the Chief Investigator of TRACERx Renal, said: “Cancer spread is one of the biggest barriers to improving survival rates. In the context of the TRACERx Renal study we previously resolved the genetic make up of different tumour areas, but until now, there has been no understanding of how these differences relate spatially. The most critical question is the part of the tumour from which cancer cells break away and migrate making cancer incurable. 

“Using this unique clinical cohort and a multidisciplinary approach, including mathematical modeling, we identified with precision the place in the tumour where genetic chaos emerges to give rise to metastases. Our observations shed light on the sort of environmental conditions that would foster emergence of aggressive behaviour. These findings are a critical foundation for considering how we target or even prevent distinct populations of cells that pose the biggest threat.”

This study involve researchers at UCL, the Crick, The Royal Marsden, and Cruces University Hospital, Spain.

The work was primarily funded by the Royal Marsden Renal Unit, the Biomedical Research Centre at the Royal Marsden and Institute of Cancer Research, Cancer Research UK, Rosetrees Trust, the National Institute for Health Research (NIHR) and the EU Framework Programme for Research and Innovation H2020. 

Links

Featured image: Cartoon summarising the differences observed between tumour centre and tumour margin, which might be explained by differences in blood supply to different parts of the tumour. © UCL


Reference: Zhao, Y., Fu, X., Lopez, J.I. et al. Selection of metastasis competent subclones in the tumour interior. Nat Ecol Evol (2021). https://doi.org/10.1038/s41559-021-01456-6


Provided by University College London

Cells From the Centre Of Tumours Most Likely to Spread Around the Body (Medicine)

Researchers from the Francis Crick Institute, Royal Marsden, UCL and Cruces University Hospital have found that cells from different parts of kidney tumours behave differently, and surprisingly, cells within the centre of a tumour are the most aggressive and have the highest chance of spreading around the body.

Cancers can spread to other parts of the body, with cells taking hold as secondary tumours which make the disease much harder to treat. Understanding the mechanics of this spread, a process called metastasis, could lead to new treatments that block this migration.

In their multidisciplinary study published today (17 May) in Nature Ecology and Evolution, scientists led by the Litchfield lab at UCL and the Turajlic, Swanton, and Bates labs at the Crick, analysed 756 cancer biopsy samples from different regions within tumours from the TRACERx Renal study.

They found that cells at the centre of tumours have a less stable genome and a higher potential to spread to secondary sites around the body. By contrast cells at the tumour edge had lower rates of metastasis, as well as lower rates of growth and genetic damage.

“Cancer cells in the central zone of the tumour face harsh environmental conditions, as there’s a lack of blood supply and oxygen. They have to adapt to survive, which makes them stronger and more aggressive. This also means they are more likely to successfully evolve into cells that can disseminate and take hold in distant organs,” says Kevin Litchfield, paper author and group leader at the UCL Cancer Institute.

The results highlight a need to pay close attention to the tumour centre to understand how cancer spreads and to find the cancer cells of greatest threat to the patient. It also shows the importance of developing treatments that target the unique environmental conditions found within the tumour core, in order to successfully eliminate the most aggressive tumour cells.

The scientists also looked at how genetically different populations of cancer cells grow within a tumour. Using a unique map building tool to reconstruct the growth of tumour cells, they found that, while most tumours follow a pattern where populations of cells grow in the local area – like a plant growing up and outwards – two cases demonstrated a “jumping” pattern where cells took hold in a new region of the tumour by seemingly ‘jumping’ over other populations of tumour cells.

The researchers are now planning to reconstruct 3D tumour maps, which will provide an even clearer visualisation of the spatial patterns within tumours.

Samra Turajlic, head of the Crick’s Cancer Dynamics Laboratory, Consultant Medical Oncologist at the Royal Marsden NHS Foundation Trust and the Chief Investigator of TRACERx Renal, said: “Cancer spread is one of the biggest barriers to improving survival rates. In the context of the TRACERx Renal study we previously resolved the genetic make up of different tumour areas, but until now, there has been no understanding of how these differences relate spatially. The most critical question is the part of the tumour from which cancer cells break away and migrate making cancer incurable.

“Using this unique clinical cohort and a multidisciplinary approach, including mathematical modeling, we identified with precision the place in the tumour where genetic chaos emerges to give rise to metastases. Our observations shed light on the sort of environmental conditions that would foster emergence of aggressive behaviour. These findings are a critical foundation for considering how we target or even prevent distinct populations of cells that pose the biggest threat.”

The work was primarily funded by the Royal Marsden Renal Unit, the Biomedical Research Centre at the Royal Marsden and Institute of Cancer Research, Cancer Research UK, Rosetrees Trust, the National Institute for Health Research (NIHR) and the EU Framework Programme for Research and Innovation H2020.


Reference: Zhao, Y. et al. (2021). Selection of metastasis competent subclones in the tumour interior. Nature Ecology & Evolution. DOI: 10.1038/s41559-021-01456-6


Provided by Francis Crick Institute

Oncotarget: Phase 1 study of Z-Endoxifen in Patients with Solid Tumors (Medicine)

Oncotarget published “Phase 1 study of Z-Endoxifen in patients with advanced gynecologic, desmoid, and hormone receptor-positive solid tumors” which reported that Z-endoxifen administration was anticipated to bypass these variations, increasing active drug levels, and potentially benefiting patients responding sub-optimally to tamoxifen.

Patients with treatment-refractory gynecologic malignancies, desmoid tumors, or hormone receptor-positive solid tumors took oral Z-endoxifen daily with a 3 3 phase 1 dose escalation format over 8 dose levels.

Three patients had partial responses and 8 had prolonged stable disease; 44.4% of patients at dose levels 6–8 achieved one of these outcomes.

Six patients who progressed after tamoxifen therapy experienced partial response or stable disease for ≥ 6 cycles with Z-endoxifen; one with desmoid tumor remains on study after 62 cycles.

The Oncotarget article provides evidence that antitumor activity and prolonged stable disease are achieved with Z-endoxifen despite prior tamoxifen therapy, supporting further study of Z-endoxifen, particularly in patients with desmoid tumors.

The Oncotarget article provides evidence that antitumor activity and prolonged stable disease are achieved with Z-endoxifen despite prior tamoxifen therapy.

Dr. Alice P. Chen from The Division of Cancer Treatment and Diagnosis at The National Cancer Institute in Bethesda Maryland said, “Tamoxifen is a member of the selective estrogen receptor modulator (SERM) drug family and is approved by the FDA for the treatment of patients with estrogen receptor-positive (ER+) metastatic breast cancer, for adjuvant therapy of high-risk ER+/progesterone receptor-positive (PR+) breast cancer, and for chemoprevention in women at high risk of developing breast cancer.

However, only about 50% of women with metastatic ER breast cancer who receive treatment with tamoxifen derive benefit, and trials have yielded mixed results regarding the clinical benefit of tamoxifen based on dose or serum concentration.

Endoxifen and 4-hydroxy-tamoxifen have similar binding affinities for ERα and ERβ, which are approximately 100-fold higher than those of tamoxifen or NDM-tamoxifen, but endoxifen plasma concentrations following tamoxifen administration are 5- to 20-fold higher than 4-hydroxy-tamoxifen.

Multiple other factors, including age, body mass index, gender, and polypharmacy contribute to how patients metabolize tamoxifen into endoxifen.

Among patients who receive tamoxifen, levels of endoxifen are lower in poor metabolizers, a finding that appears to correlate with significantly reduced time to tumor recurrence in these patients compared to those with greater CYP2D6 metabolism following treatment with adjuvant tamoxifen.

The Chen Research Team concluded in their Oncotarget Research Output that additional preclinical and clinical data demonstrate that Z-endoxifen can elicit major responses in ER breast cancer that has progressed on tamoxifen.

Despite these data in breast cancer, the optimal dose or concentration of Z-endoxifen in other tumors is unknown; however, our observation that high dose Z-endoxifen elicits antitumor activity in patients with non-breast malignancies would be in keeping with the data already observed demonstrating Z-endoxifen antitumor activity in breast cancers that have progressed on tamoxifen.

Furthermore, the overall safety profile, achievable plasma concentrations of Z-endoxifen, and clinical efficacy seen in this trial indicate that this agent may particularly benefit patients who have progressed on tamoxifen treatment and suggest that further studies of Z-endoxifen should be considered in patients with non-breast malignancies.

DOI – https://doi.org/10.18632/oncotarget.27887

Full text – https://www.oncotarget.com/article/27887/text/

Featured image: Number of cycles completed by each evaluable patient. Colors indicate the diagnosis of each patient as indicated. Asterisks indicate patients who had previously progressed on tamoxifen therapy. © Authors


Reference: Takebe N., Coyne G. O’Sullivan, Kummar S., Collins J., Reid J. M., Piekarz R., Moore N., Juwara L., Johnson B. C., Bishop R., Lin F. I., Mena E., Choyke P. L., et al Phase 1 study of Z-endoxifen in patients with advanced gynecologic, desmoid, and hormone receptor-positive solid tumors. Oncotarget. 2021; 12: 268-277. Retrieved from https://www.oncotarget.com/article/27887/text/


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