Tag Archives: #cancer

New Therapeutic Target Discovered For A Number Of Aggressive Cancers (Medicine)

An RNA-modifying protein elevated in some aggressive cancers has been shown to be a promising target for new drug development 

A protein in tumor cells could be targeted to treat some types of aggressive cancer including brain, blood, skin, and kidney, new research has shown.

The scientists, from the Wellcome Sanger Institute, University of Cambridge and Harvard University, have identified a protein that plays a key role in transforming normal tissue into cancer, as a possible target for drug development. Inhibiting this protein effectively destroys cancer cells in laboratory models, including in cell lines and mice, while leaving healthy cells unharmed.

The research, published today (4 August 2021) in Molecular Cell, provides strong evidence that developing drugs that block the RNA-modifying protein known as METTL1 could give people with aggressive brain, blood, skin, and kidney cancers new treatment options.

RNA-modifying proteins, in particular the METTL family, are involved heavily in cell replication. These proteins have been found in higher levels in certain cancer cells, including some brain, blood, pancreatic, and skin cancers, and are associated with poorer outcomes.

Previously, Dr. Tzelepis, along with his team at the University of Cambridge, and their collaborators at the Wellcome Sanger Institute, used CRISPR-Cas9 gene-editing technology to screen cancer cells for vulnerable points. The researchers identified the METTL1 gene—a gene that produces the RNA-modifying METTL1 protein—as a target for drug development.

In a new study that builds on that research, researchers at the Wellcome Sanger Institute, University of Cambridge, and Harvard University have now found that mutations in the METTL1 gene which lead to higher levels of the METTL1 protein, cause the cells to replicate faster and transform into a cancerous state, producing highly aggressive tumors.

When the team inhibited the METTL1 protein by knocking out the gene, it stopped cancer cell growth while leaving the normal healthy cells unharmed, in both laboratory and mice models, suggesting it would be a good target for cancer treatments.

Recently, the team also developed a small-molecule inhibitor for a similar protein, METTL3, to help treat acute myeloid leukemia, which will be entering clinical trials in 2022. It is hoped that this new research provides the evidence needed to start to develop a similar drug that targets METTL1, which could be used to treat a wider range of aggressive cancers if they have a mutation in the METTL1 gene or high levels of its protein.

As the METTL1 protein is elevated in cancer cells with poorer outcomes, it could also be used as a biomarker to inform treatment plans and identify those who would benefit if a drug was developed, to ensure clinical trials are as streamlined and personalized as possible.

Professor Richard Gregory, co-lead author and Principle Investigator at Boston Children’s Hospital and Harvard Medical School, Boston, said: “Cancer cells benefit from an unregulated cell cycle, leading to increased replication, and while some of the reasons behind this are known, there is still a lot to discover. This research illuminates deeply the role of the METTL1 protein in cancer development and proves that mutations in this gene can cause a cell to become cancerous. The more we understand about the genetic basis of cancer and how we can combat this, the more life changing targeted treatments we can create.”

Dr. Esteban Orellana, first author and Research Fellow at Boston Children’s Hospital, said: “Our research gives incredibly strong evidence that targeting the RNA modifying protein, METTL1, is an effective treatment against certain cancers, helping to kill cancer cells while leaving the other cells in the body untouched. This is important as it could mean that there will be fewer unpleasant side effects of a potential new treatment. The next step for this research is to try and develop a small molecule inhibitor to block METTL1 to see if our encouraging results can be translated across to the clinic.”

Dr. Konstantinos Tzelepis, co-lead author, group leader at the University of Cambridge and visiting scientist at the Wellcome Sanger Institute said: “This study provides another great example of what is possible with the use of CRISPR technologies and how we can take and prioritize precise genetic information and turn it into something of potential clinical benefit. Targeting RNA-modifying proteins can effectively destroy cancer cells and we hope that this research will provide the evidence necessary for drugs to be developed that target METTL1, potentially providing a new therapy against aggressive cancers with clear and unmet therapeutic need.”


References: (1) METTL1-mediated m7G modification of Arg-TCT tRNA drives oncogenic transformation, Molecular Cell (2021). DOI: 10.1016/j.molcel.2021.06.031 (2) Tian, Q.H., Zhang, M.F., Zeng, J.S., Luo, R.G., Wen, Y., Chen, J., Gan, L.G., and Xiong, J.P. (2019). METTL1 overexpression is correlated with poor prognosis and promotes hepatocellular carcinoma via PTEN. J Mol Med (Berl) 97, 1535-1545. DOI: 10.1007/s00109-019-01830-9 (3) Tzelepis K, Koike-Yusa H, De Braekeleer E, Li Y, Metzakopian E, Dovey OM, Mupo A, Grinkevich V, Li M, Mazan M et al.(2016) A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia. Cell reports. 17;4;1193-1205. (4) Barbieri I, Tzelepis K, Pandolfini L, Kouzarides T, et al. (2017) Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control. Nature. 27;552(7683):126-131. DOI: 10.1038/nature24678


Provided by Wellcome Trust Sanger Institute

Oncotarget: Telomere Dysfunction and Chromosome Instability in Cancer Cells (Biology)

Oncotarget published “Terpyridine platinum compounds induce telomere dysfunction and chromosome instability in cancer cells” which reported that this assay is based on the use of two isogenic HT1080 cell lines, one carrying a linear HAC and the other carrying a circular HAC.

Disruption of telomeres in response to drug treatment results in specific destabilization of the linear HAC.

In this study, they used the dual-HAC assay for the analysis of the platinum-derived G4 ligand Pt-tpy and five of its derivatives: Pt-cpym, Pt-vpym, Pt-ttpy, Pt -tpy, and Pt-BisQ. Their analysis revealed four compounds, Pt-tpy, Pt-ttpy, Pt-vpym and Pt-cpym, that induce a specific loss of a linear but not a circular HAC.

Increased CIN after treatment by these compounds correlates with the induction of double-stranded breaks predominantly localized at telomeres and reflecting telomere-associated DNA damage.

These terpyridine platinum-derived G4 ligands are promising compounds for cancer treatment.

These terpyridine platinum-derived G4 ligands are promising compounds for cancer treatment.

Dr. Vladimir Larionov and Dr. Natalay Kouprina both from The National Institutes of Health said, “Normal human somatic cells contain 46 chromosomes.

Telomerase/telomere-targeting therapy is considered to be a potentially promising approach for cancer treatment because even transient telomere dysfunction can induce chromosomal instability in human cells.

The enzyme telomerase elongates telomeres and maintains a telomere length equilibrium that prevents telomeres from becoming critically short.

In particular, formation of G4s at telomeres could impede telomerase recognition and inhibit telomere elongation leading to telomere shortening.

Thus, telomeres are promising targets for discovery of ligands that stabilize G4s at telomeres, thereby perturbing telomere maintenance and leading to genomic instability.

The authors found that treatment of cancer cells with either Pt-cpym, Pt-vpym, Pt-ttpy or Pt-tpy induces telomere dysfunction leading to high levels of chromosome instability.

The Larionov/Kouprina Research Team concluded in their Oncotarget Research Output, “using our dual-HAC assay we identified three terpyridine platinum compounds, Pt-tpy, Pt-vpym and Pt-cpym, that induce a high level of chromosome instability (CIN) as previously reported for the related compound Pt-ttpy. CIN observed after treatment of cells with these compounds correlates with the formation of double-stranded DNA breaks predominantly localized proximal to telomeres. The telomere-associated DNA damage induced by these drugs leads to chromatin bridge formation in late mitosis and cytokinesis. This family of G4 ligands that induce telomere dysfunction and greatly increase chromosome mis-segregation rates are promising drug candidates for treatment of cancer alone or in combination with ionizing radiation.

DOI – https://doi.org/10.18632/oncotarget.28020

Full text – https://www.oncotarget.com/article/28020/text/

Featured image: Specific telomere aberrations in HT1080 cells induced by treatment of Pt-tpy and its derivatives, Pt-cpym, Pt-vpym and Pt-ttpy. (AC) Histograms show the percentages of chromosomes with the indicated telomere damage per cell detected in metaphase spreads of treated versus untreated cells (DMSO) hybridized with a telomeric PNA probe (in red) and then counterstained with DAPI (in blue). *Indicates a t-test P-value < 0.05; **P < 0.01. (D and E) Representative images of the different telomere aberrations after Pt-ttpy treatment. TD-telomere doublets; STL-single telomere loss; SCF-sister chromatid fusion; DEL-terminal deletion. © Correspondence to – Vladimir Larionov – larionov@mail.nih.gov and Natalay Kouprina – kouprinn@mail.nih.gov


Reference: Petrov N., Lee H., Liskovykh M., Teulade-Fichou M., Masumoto H., Earnshaw W. C., Pommier Y., Larionov V., Kouprina N. Terpyridine platinum compounds induce telomere dysfunction and chromosome instability in cancer cells. Oncotarget. 2021; 12: 1444-1456. Retrieved from https://www.oncotarget.com/article/28020/text/


Provided by Impact Journals LLC

A Lot Of Body Fat Increases The Risk Of Cancer of the Digestive Organs (Biology)

Obesity increases the risk of cancer of the digestive tract and it is the amount of body fat rather than the size of the person that is the main obesity-related risk factor for these types of cancer. This is shown by a new study published in the journal PLOS Medicine by researchers at the University of Cambridge and Karolinska Institutet.

Susanna Larsson. Photo: Anna Persson.

Previous observational studies have shown that a high BMI (body mass index) is linked to several cancers.

In the new study, researchers have used data from UK Biobank and large international consortia and a method called Mendelian randomization to investigate which types of cancer have a causal relationship between body size and cancer risk and how different components such as body fat, BMI and height affect this risk.

The researchers studied whether individuals with gene variants that are linked to high BMI, high body fat or above-average body length also have an increased risk of developing 22 different types of cancer.

– Body weight is often affected by the presence of cancer or by cancer treatment. Looking at genes rather than an individual’s height or weight reduces the risk of finding connections in observational data that are not causal, says Susanna Larsson , associate professor at the Institute of Environmental Medicine at Karolinska Institutet and shared last author of the article.

BMI and cancer of the digestive tract

Genetic propensity to be long was associated with a slightly increased risk for all different categories of cancer. Genetic predisposition to high BMI was mainly linked to an increased risk of cancer of the digestive organs, especially cancer of the liver, stomach, esophagus and pancreas.

The increased risk of cancer of the digestive organs could mainly be explained by gene variants that give an increased tendency to a lot of body fat.

– This means that body fat is a more important risk factor than body size and that high BMI is not necessarily a risk factor for many different types of cancer, but mainly for cancer of the digestive organs, says Susanna Larsson.

Genetic predisposition to high BMI was also linked to an increased risk of cancer of the uterus, ovaries and lungs, but a reduced risk of breast and prostate cancer.

Higher risk with more cells in the body

The study does not show the mechanisms behind the associations, but one hypothesis is that tall people have a higher risk of cancer because they have more cells in the body. According to the researchers, the link between body fat and cancer in the digestive organs may be due to greater consumption of carcinogens in fatty foods, or that more adipose tissue causes increased inflammation in the gastrointestinal tract.

The link between obesity and sex-specific cancers is likely to be affected by the production of sex hormones in adipose tissue.

The study was conducted in collaboration with researchers at the University of Cambridge and Bristol, UK. The researchers have not received any specific funding for the study.

Featured image: Illustration: Getty Images.


Publication

“Body size and composition and risk of site-specific cancers in UK Biobank and large international consortia: a Mendelian randomization study” . Mathew Vithayathil, Paul Carter, Siddhartha Kar, Amy M. Mason, Stephen Burgess, and Susanna C. Larsson. PLOS Medicine , online July 29, 2021, doi: 10.1371 / journal.pmed.1003706.


Provided by Karolinska Institute

Researchers Uncover New Understanding Of Cancer Cell Telomere Survival Mechanisms (Medicine)

Case Comprehensive Cancer Center-led research has potential for development of new cancer treatment targets.

Research published in “Science Signaling” identifies new ways that telomeres regulate the aggressiveness and survival of tumors, making them potentially vulnerable therapeutic targets for killing cancer. The discovery was made by a team of researchers at the Case Comprehensive Cancer Center and the Case Western Reserve School of Medicine while studying how cancer cells switch telomere regulation and maintenance mechanisms during disease development and response to therapy.

Telomeres are the ends of chromosomes made of non-coding DNA. When normal cells divide, their telomeres become shorter until the cell can no longer divide. However, cancer cells can keep their telomeres long, extending their life indefinitely by activating one of two processes, either telomerase or the Alternative Lengthening of Telomeres (ALT) pathway.

The team, led by William Schiemann, PhD, Goodman-Blum Professor in Cancer Research, Case Comprehensive Cancer Center, School of Medicine, delineated a pathway by which ALT is regulated – a mechanism that has not been well understood before. In addition, the team discovered the machinery that regulates ALT not only oversees telomere length but also functions in the cytoplasm to regulate signaling pathways associated with disease progression, cancer stem cells, and chemoresistance. Their findings lead them to believe it is possible to target these new pathways to alleviate different cancers. 

“This may be a unique opportunity to treat a tumor one way based on its predominant maintenance mechanism, knowing that when they develop resistance and flip to the other maintenance mechanism that we’ll be able to hit them with the highly effective treatment,” said Schiemann. 

Though the research is still in the lab investigation stage, in the future, Schiemann said he would like to move to a proof-of-concept phase one clinical trial to test the patient’s sensitivity to these inhibitors. Ideally, Schiemann said that therapeutic targeting of telomere maintenance mechanisms, particularly in adjuvant settings, has the potential to eliminate disease recurrence and metastatic relapse.

Co-authors on the paper include Case Comprehensive Cancer Center members Masaru Miyagi, PhDJacob G. Scott, MD, PhD, and Derek J. Taylor, PhD; trainees Nathaniel J. Robinson, PhD and Jessica A. Scarborough. 


Reference: Nathaniel J. Robinson et al, SLX4IP promotes RAP1 SUMOylation by PIAS1 to coordinate telomere maintenance through NF-κB and Notch signaling, Science Signaling (2021). DOI: 10.1126/scisignal.abe9613


Provided by Case Western Reserve University

Researchers Synthesized Biological Compound Which Kill Cancer Cells Without Harming The Heart (Medicine)

With modern-day cancer therapeutics presenting adverse side effects to heart health, scientists are studying methods to attack cancer cells without the risk of damaging the heart. Researchers Steven Townsend, associate professor of chemistry, and Neil Osheroff, John Coniglio Professor of Biochemistry and professor of medicine, synthesized the biological compound arimetamycin A, shown to kill cancer cells in mice without harming the heart.

Natural isolated products from soil bacteria known as anthracyclines are currently being used as cancer therapeutics.  Chosen because of their inexpensive cost and high level of toxicity to tumors, specific anthracyclines, including doxorubicin and daunorubicin, also attack the heart in the process of killing cancer. To synthesize arimetamycin A, Townsend and his team modified the carbohydrate, or sugar, portions of anthracyclines and then fine-tuned their activity, increasing toxicity levels toward cancer cells while decreasing the adverse effects on the heart. The synthesis and promising results could lead to less harmful cancer drug discovery.

“One molecule [of doxorubicin] kills 10 cancer cells. Our improvement to the drug can kill 1,000,” Townsend said.

According to Townsend, in a clinical setting medical doctors play a delicate game when prescribing medication to kill cancer. They aim to prescribe enough to kill the cancer but not in an amount that could potentially harm the heart. With the synthesis of less cardiotoxic drugs, the future of healthier cancer therapeutics advances forward.

For decades, researchers have struggled with the improvement of drugs due to a lack of technology and resources. The difference between then and Townsend and Osheroff’s current discovery lies in access to molecular modeling, cellular-level imaging techniques and a deeper understanding of how these drugs work.

Chemists continue to build upon not only new discoveries but also standstills from previous research endeavors that advance our understanding of cancer therapeutics. “In 2021, we have a much better idea of exactly how these [drugs] slide and bind to DNA compared to previous decades. With that enhanced understanding, we know how to modify the drugs to fine-tune their activity,” Townsend said. “If you look at most famous chemists now, they are excellent at going back to the literature to see what ideas people had then that they couldn’t figure out. Modern skillsets, tools and better technology help us do this in a more designed way.”

Even though the research team validated that arimetamycin A is more cytotoxic than current cancer therapeutics, Townsend aims to further increase the drug’s toxicity levels while decreasing cardiotoxicity. Another avenue for new research will involve attaching the new anthracyclines (known as a payload) to an antibody, to study targeted delivery of the drug to tumors. These antibody-drug conjugates allow increased drug levels at the tumor site while avoiding cardiotoxicity completely.


Reference: Eric D. Huseman et al, Synthesis and Cytotoxic Evaluation of Arimetamycin A and Its Daunorubicin and Doxorubicin Hybrids, ACS Central Science (2021). DOI: 10.1021/acscentsci.1c00040


Provided by Vanderbilt University

Cancer Vaccine Improves Outcomes in Lynch Syndrome Model (Medicine)

A new strategy for developing vaccines against cancer showed promise in a proof-of-concept study led by scientists at Weill Cornell Medicine, NewYork-Presbyterian and Heidelberg University Hospital.

The preclinical results could eventually lead to vaccines that cause the immune system to target cancers early in their development, preventing the disease from becoming established.

The study, published July 2 in Gastroenterology, found that the vaccine reduced the tumor burden, prompted an immune response to cancerous cells and improved overall survival in an animal model of Lynch syndrome, the most common genetic predisposition to gastrointestinal cancer.

Cancer vaccines are not a new idea. As part of their development, cancer cells often express proteins on their surface that don’t normally appear on healthy cells. The immune system can naturally detect these abnormal antigens and destroy the tumors before they get established.

This “immune surveillance” process isn’t perfect, though, and it tends to weaken with age. In theory, a cancer vaccine could boost immunity against a particular type of tumor and reinvigorate immune surveillance against it. In practice, that approach has been hard to implement.

“There have been many trials that have tried to use cancer vaccines as a therapy, not as a prevention, but those have largely been unsuccessful,” said senior author Dr. Steven Lipkin, vice chair for research in the Sanford and Joan Weill Department of Medicine at Weill Cornell Medicine and a medical geneticist at NewYork-Presbyterian/Weill Cornell Medical Center.

That’s because once tumors become established, they often develop strategies to suppress or evade the patient’s natural immune response against them, rendering vaccines ineffective. “However, we’ve known for many years that when cancers first start, when they’re at the level of a single cancer cell that has just transformed or a few cancer cells, that’s when they’re most vulnerable,” said Lipkin, who is also the Gladys and Roland Harriman Professor of Medicine at Weill Cornell Medicine.

To begin developing a preventive cancer vaccine, Lipkin and his colleagues and collaborators targeted Lynch syndrome. About one in 280 people carry Lynch syndrome mutations, which cause defects in their DNA repair systems. Faulty repair of mutations during normal cell division predisposes them to cancer, especially in the intestinal tract. The mutations also cause the cancer cells to produce altered proteins, or neoantigens, that can be targeted by the immune system.

Using a mouse model of Lynch syndrome, the investigators identified the most common neoantigens that appeared in the animals’ tumors. “We then used computational methods to predict which of those would be the most effective in a vaccine,” Lipkin said.

That process yielded four neoantigens that were widespread in the mouse tumors and also capable of stimulating strong immune responses. When the team vaccinated the Lynch syndrome mice with a combination of those four protein antigens, the animals developed robust immune responses against them, and subsequently had lower tumor burdens and survived longer than unvaccinated mice.

The scientists have already started moving into human studies. A pioneering phase 1/2a clinical trial initiated by Heidelberg University Hospital demonstrated that neoantigen peptide vaccines are feasible and induce strong immune responses. In an alternative approach, Italian biotechnology company Nouscom has used an adenovirus-based vaccine – conceptually similar to the technology behind some of the major COVID-19 vaccines now in widespread use – to immunize patients with Lynch syndrome and advanced gastrointestinal tumors.

“It seems to be safe, which is good,” Lipkin said. He added that a larger study to test the efficacy of a Lynch syndrome tumor vaccine should get underway in 2022. Besides the adenovirus platform, Lipkin and his colleagues are also looking into developing messenger RNA-based cancer vaccines.

Even modest success in the clinic could have a big impact. “I’m not trying to say at all that this is the end of cancer, but … even if you can reduce it by 10%, that’s millions of lives saved, and if we can do it with minimal side effects, hopefully, that would be a godsend,” Lipkin said.


Provided by Cornell University

Mayo Clinic Scientists Advance Breast, Ovarian Cancer Research With Cryo-electron Microscopy (Medicine)

Using advanced imaging technology, Mayo Clinic scientists have provided an unprecedented understanding of the BRCA1-BARD1 protein complex, which is often mutated in patients with breast or ovarian cancer. Their paper, published in Nature, identifies aspects of how BRCA1-BARD1 functions, supporting future translational research, cancer prevention efforts and drug development.

“BRCA1-BARD1 is important for DNA repair. It has direct relevance to cancer because hundreds of mutations in the BRCA1 and BARD1 genes have been identified in cancer patients,” says Georges Mer, Ph.D., a Mayo Clinic structural biologist and biochemist who is the lead author of the paper. “But no one knows if these mutations, or variants of unknown significance, are cancer-predisposing or not because we do not know whether the variants are located in a region of BRCA1-BARD1 that is important for function. Now because we can see how BRCA1-BARD1 works, we have a good idea of what regions of BRCA1-BARD1 are important for function.”

In a cell, the complex of DNA and histone proteins are complexed into what’s called chromatin, and packaged into bundles called nucleosomes:

Image by Mayo Clinic, created with BioRender.
Image by Mayo Clinic, created with BioRender.

DNA damage response proteins need to access chromatin to repair damaged DNA. BRCA1-BARD1 contributes to fixing broken DNA strands, which helps in the maintenance and survival of cells. But it is also a function that could possibly be blocked or inactivated if this is a strategy a cancer cell uses to survive chemotherapy.

Cryo-electron microscopy and nuclear magnetic resonance spectroscopy

“We used two techniques ― cryo-electron microscopy and nuclear magnetic resonance spectroscopy ― to understand at near-atomic resolution how BRCA1-BARD1 associates with the nucleosome, the repeating unit of chromatin, and how BRCA1-BARD1 modifies chromatin,” explains Dr. Mer.

In cryo-electron microscopy, purified BRCA1-BARD1 bound to nucleosomes, together referred to as macromolecules, are flash-frozen then imaged using an electron microscope. The macromolecules are oriented in various ways within the sample so a computer program evaluates all the orientation data to create a 3D structure. Dr. Mer and his team also examined BRCA1-BARD1 nucleosome complexes with nuclear magnetic resonance spectroscopy, which uses a strong magnet to probe the relative positions of atoms within macromolecules. Using these imaging tools, the scientists could visualize BRCA1-BARD1 in action and uncover a new function of the complex:

Image by Mayo Clinic, created by Dr. Mer.
Image by Mayo Clinic, created by Dr. Mer.

“We showed how BRCA1-BARD1 attaches ubiquitin to the nucleosome, but we also determined that BRCA1-BARD1 recognizes ubiquitin already attached to the nucleosome, which serves as a signal for broken DNA,” says Dr. Mer. “We discovered an unexpected cross-talk by which ubiquitin recognition by BRCA1-BARD1 enhances its ubiquitin attachment activity, and this helps us better understand how BRCA1-BARD1 performs its function.”

The researchers created a video from the cryo-electron microscopy data to show where the protein complex interacts with the nucleosome:

From discovery science to patient care

Dr. Mer and his team expect that high-resolution images of BRCA1-BARD1 can help guide patient care and future treatment of cancer in two ways: classifying variants of unknown significance and directing drug development with more accuracy.

“With these 3D structures, we should be able to convert several variants of unknown significance to likely cancer-predisposing variants,” says Dr. Mer. “This work is also expected to have an impact on drug development in the long term because the 3D structures of BRCA1-BARD1 in complex with the nucleosome we generated may help in the design of small molecules that could, for example, inactivate BRCA1-BARD1.”

In addition to Dr. Mer, other authors on the paper are Qi Hu, Ph.D.; Maria Victoria Botuyan, Ph.D.; Debiao Zhao, Ph.D.; Gaofeng Cui, Ph.D.; and Elie Mer. This research was funded by the National Institutes of Health, Mayo Clinic Cancer CenterMayo Clinic Center for Biomedical Discovery, and the Ovarian Cancer Research Alliance, and was made possible through cryo-electron microscopy and nuclear magnetic resonance instrumentation at the Pacific Northwest Center for Cryo-EM and Mayo Clinic, respectively.


Reference: Hu, Q., Botuyan, M.V., Zhao, D. et al. Mechanisms of BRCA1–BARD1 nucleosome recognition and ubiquitylation. Nature (2021). https://doi.org/10.1038/s41586-021-03716-8


Provided by Mayo Clinic

Heated Chemotherapy Can Help Some Children With Cancer (Medicine)

Known as HIPEC, the therapy has been available for adults for years at Michigan Medicine. Now it’s an option for kids here, too.

Tumors that have spread to the lining of the abdomen are tough to treat. But a select number of cancer teams across the country have found success with a procedure known as HIPEC, which stands for hyperthermic intraperitoneal chemotherapy, a method of pumping heated chemo directly into the belly instead of sending it through the bloodstream. 

Michigan Medicine surgeons have used this technique for several years in adults but are just starting to provide it to children. Erika Newman, M.D., an associate professor of pediatric surgery at the University of Michigan Medical School and the associate chief clinical officer of health equity for Michigan Medicine, sat down with Michigan Health to explain the situations where HIPEC might be useful, what considerations are important for the procedure in kids and why Michigan Medicine’s multidisciplinary team is so crucial when performing this complex technique.

What does HIPEC stand for and why would heated chemotherapy be more effective than other types of chemotherapy in certain situations?

It stands for hyperthermic or heated intraperitoneal chemotherapy or chemoperfusion.

HIPEC is administered directly into the abdomen. It’s not absorbed into the bloodstream, and so it has fewer side effects on the rest of the body. That is one really important characteristic, especially for kids, because one of the aspects of cancer treatment that limits us is systemic toxicity — the total amount of harmful substances the body can endure before severe side effects develop.

Pediatric cancers that attach to the lining of the abdomen — we call that the peritoneum — and its surfaces are the best candidates because you’re instilling that chemotherapy directly into the abdomen, so it can penetrate those surfaces directly as opposed to going through the bloodstream and attacking cancer cells on the surface.

What type of cancers are appropriate for HIPEC treatment?

The most common peritoneal cancer in children and young adults that benefit from this kind of therapy is a tumor called desmoplastic small round cell tumor or DSRCT. It’s a very rare but very aggressive form of cancer. The patients with this condition that have the best chance at long-term survival and have the best outcomes are the ones in which we are able to remove all of the tumor from the abdomen, including where the tumor has attached to the lining of the peritoneum, and then combine that with HIPEC. Those patients have been shown to have better outcomes than the patients that don’t have HIPEC.

For this kind of cancer, HIPEC is a component of what we would now consider first-line therapy, or the first treatment given for a disease because it’s widely considered the best option.

Most DSRCT patients get chemotherapy before surgery, known as neoadjuvant chemotherapy. They get anywhere from five to six cycles of chemotherapy, and then we go into what we call a local control surgery, where we remove the tumor along with giving HIPEC. And then they’ll get what we call adjuvant therapy, or the chemotherapy that is given after the initial treatment and primary surgery. So essentially, the kids get really high doses of intense chemo to try to get long-term cures for some of these really tough cancers

Is HIPEC ever used as a secondary option if other treatments don’t work?

It certainly can be for recurrent disease and in patients with disease that comes back in the abdomen. It can be a treatment for other conditions, too.

Kids don’t typically get colon cancer, but HIPEC can be used for metastatic colon cancer. For children, HIPEC can also be used for certain types of sarcomas that have spread to the peritoneal surfaces. In fact, the first pediatric HIPEC case we did was for a child with a sarcoma.

Another condition HIPEC can be used to treat would be malignant ovarian germ cell tumors, in which cancer forms in the germ, or egg, cells of the ovary. Those tumors can attack the peritoneal lining. So really any tumor that involves the peritoneum or the peritoneal lining would be an ideal case for HIPEC.

What’s different about the procedure in kids?

First off, kids are kids — not small adults.

Second, all patients receiving HIPEC have a risk of renal failure. But children have an even more pronounced risk of renal failure with HIPEC than adults. So we do several things during our pediatric HIPEC cases to make sure that we protect their kidneys during and after the operation. This includes special medications and fluid orders.

In general, kids are smaller, so we need to ensure we have the proper pediatric-sized cannulas (tubes that are inserted into a vein or body cavity for various purposes, including to administer medication). The other things that we’re thinking about are dosing — making sure we have the right doses and volumes of the chemotherapy appropriate for the size of the patient we are treating. Our chemotherapy Pharm.D. and oncology pharmacists are instrumental and are front and center in helping us navigate chemo doses and intraperitoneal chemotherapy orders.

“It’s very clear now that we can try to increase survival in kids that have really tough cancers where, if you don’t attempt this, then there really are not any more treatment options. Being able to give a family hope is really important.” said Erika Adams Newman, M.D.

Is that level of multidisciplinary expertise something that differentiates Michigan Medicine from some other health centers?

Absolutely! Getting us to and through the first two pediatric HIPEC cases at Michigan Medicine exemplified how phenomenally our multidisciplinary and interdisciplinary teams come together. Every service approached to assist with our initiative and ongoing efforts were excited and passionate about coming together to provide this potentially curative procedure to our pediatric population. The HIPEC pediatric procedure included:

  • Pediatric oncology
  • Pediatric surgery
  • Pediatric anesthesiology
  • The adult peritoneal malignancy program
  • The pediatric intensive care unit and the pediatric critical care medicine team
  • Pediatric oncology pharmacists and adult HIPEC pharmacists
  • Nursing teams in the operating rooms
  • Surgical technicians in the operating rooms
  • Perfusionists, who specialize in bathing organs or tissues in fluid, and who helped with perfusing HIPEC
  • The learners that were involved in the case, i.e., medical students
  • The solid tumor program coordinator and program director

The list is huge. You need people with very specialized expertise to do this, and we have that here at C.S. Mott Children’s Hospital. Our pediatric oncologists are some of the best in the country to take care of kids with cancer. And we have a full team of experts that can band together and assure that the children are getting the highest level of care in the safest and most effective way possible, so we can hopefully have a curative outcome.

What side effects do you have to consider when administering HIPEC to children?

The biggest one is renal failure in kids because of the toxicity of the chemotherapy on the kidneys. The other thing that we deal with is post-op ileus. That’s when the bowels go to sleep and stop working. That’s a real concern afterwards. So we don’t feed the kids afterward. We just keep them hydrated with IV fluids and wait for the bowel function to return. Sometimes even five to seven days after surgery, we’re  still waiting. 

But once we can make sure their hydration status is good, their kidneys are still healthy and working, and their ileus has resolved, then we can start ushering them back into where they were pre-operatively. By that point, they’re eating and drinking and peeing and pooping and all the things are working, and then they go home.

Why did you decide to expand into HIPEC for kids this year?

HIPEC in general, even for adults, is a fairly new technique.

Up until recently, pediatric HIPEC work has been pioneered by Andrea Hayes-Jordan, a pediatric surgeon who was at MD Anderson for many years. Her area of expertise was in the benefits of HIPEC for kids with particular cancers, especially DSRCT. Her research has shown that there is survival benefit both for local occurrence and in long-term overall survival, and that work has been over the past 10 years.

It’s very clear now that we can try to increase survival in kids that have really tough cancers where, if you don’t attempt this, then there really are not any more treatment options. Being able to give a family hope is really important.

Over these last several years, more centers have been working toward being able to offer HIPEC. It just so happened that we had two kids in the last couple of months that were good candidates, and we thought now is the time.

What’s the timeline for whether you know if the HIPEC treatment was successful or not for these two initial patients?

They’re going to finish out the rest of their chemotherapy for now. Most of the time with cancer, you’re doing surveillance for the first five years after. Three years and five years are the benchmarks where we’ll know if it made a difference. But we already feel our efforts were successful by being able to offer our patients the option of HIPEC treatment when there were not a lot of other treatment options available.


Provided by University of Michigan

New Technology For Cell Therapy Shows Potential Against Hard To Treat Cancers (Medicine)

A new technology for cellular immunotherapy developed by Abramson Cancer Center researchers at Penn Medicine showed promising anti-tumor activity in the lab against hard-to-treat cancers driven by the once-considered ‘undruggable’ KRAS mutation, including lung, colorectal, and pancreatic.

The study, published online in Nature Communications, successfully demonstrated using human cells that a T-cell receptor, or TCR, therapy could be designed to mobilize an immune system attack on mutated KRAS solid tumors and shrink them. The preclinical work has laid the groundwork for the first-in-human clinical trial now in the planning stages for the treatment of advanced pancreatic cancer in patients whose tumors harbor specific KRAS mutations and express a specific type of human leukocyte antigen, or HLA, the therapy is built to recognize.

“We’ve shown that targeting mutant KRAS immunologically is feasible and potentially generalizable for a group of patients with lung, colorectal and pancreatic tumors,” said senior author Beatriz M. Carreno, Ph.D., an associate professor of Pathology and Laboratory Medicine in the Perelman School of Medicine at the University of Pennsylvania and a member of the Center for Cellular Immunotherapies, the Abramson Cancer Center, and Parker Institute for Cancer Immunotherapy at Penn. “We look forward to taking this research to the next level and closer to clinical study.”

KRAS mutations are among the most prevalent mutations observed in cancers and have been shown to drive tumor development and growth. Only recently have targeted therapies been shown to successfully treat a specific KRAS mutation found most commonly in lung cancer; however, no treatments currently exist for the majority of other KRAS mutations more prevalent in other tumor types. Immunological targeting of mutant KRAS represents an alternative treatment approach but has been less studied and understood.

Using a multiomics approach, the Penn team identified specific neoantigens associated with mutations at the G12 site on the KRAS gene. Neoantigens are protein fragments that form on the cancer cell surface when certain mutations occur in tumor DNA. More than 75 percent of the alterations in the KRAS protein occur at G12, making it an ideal site to target with therapies.

Armed with this knowledge, the researchers tested a TCR therapy directed toward specific KRAS G12 mutations present in conjunction with particular HLA types highly prevalent among patients. They showed in a mouse tumor model that it was effective at attacking and eliminating tumor cells. HLAs are an important part of the immune system because they encode cell surface molecules that present specific neoantigens to the T-cell receptors on T cells.

In other words, HLAs are key genetic codes needed for these engineered T cells to find and attack tumors.

The research further supports the use of neoantigens for targeting tumor cells, for both cellular therapy and cancer vaccines, which have been underway at Penn Medicine and elsewhere.

Importantly, the neoantigen and HLA information from this latest study is being used to develop TCR therapies to treat solid tumors, as well as new cancer vaccines. Based off these latest findings, the team initiated a vaccine clinical trial led by Mark O’Hara, MD, an assistant professor of Hematology-Oncology at Penn and co-author on the study, in pancreatic cancer targeting mutated KRAS.

The first clinical trial for the TCR therapy is projected to launch as soon as 2022, depending on regulatory approval, at Penn’s Abramson Cancer Center for patients with advanced pancreatic cancer who have both the KRAS mutation and specific HLA types identified in this latest study—which could represent up to 10 percent of patients with pancreatic cancer. The study opens the door, however, to expand the patient population as researchers continue to discover more about the neoantigens derived from regions of the KRAS gene and other mutated oncogenes implicated in driving cancer.

“We provide evidence that this oncogenic protein is a very promising clinical target of immune-based therapies,” said lead author Adham Bear, MD, Ph.D., an instructor in the division of Hematology-Oncology at Penn and member of the Parker Institute for Cancer Immunotherapy at Penn. “The goal, now that we have identified these neoantigens and T cell receptors, is to translate these findings and apply them to develop new therapies at Penn.”

Robert H. Vonderheide, MD, DPhil, director of the Abramson Cancer Center, and Gerald P. Linette, MD, Ph.D., a professor of Medicine in the Perelman School of Medicine, serve as co-authors.


Reference: Adham S. Bear et al, Biochemical and functional characterization of mutant KRAS epitopes validates this oncoprotein for immunological targeting, Nature Communications (2021). DOI: 10.1038/s41467-021-24562-2


Provided by Perelman School of Medicine at the University of Pennsylvania