Tag Archives: #chemotherapy

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

Ficlatuzumab Plus Chemotherapy May Benefit Patients With Relapsed/Refractory AML (Medicine)

Bottom Line: The investigational therapeutic ficlatuzumab in combination with chemotherapy showed signs of clinical efficacy in patients with relapsed/refractory acute myeloid leukemia.

Journal in Which the Study was Published: Blood Cancer Discovery, a journal of the American Association for Cancer Research

Author: Senior author Charalambos Andreadis, MD, professor of clinical medicine at the University of California, San Francisco (UCSF), and first author Victoria Wang, MD, PhD, an assistant professor of hematology and oncology at UCSF

Background: “Only about half of patients with acute myeloid leukemia (AML) will achieve long-term disease control,” said Andreadis. Patients whose AML relapses or does not respond to initial therapy have worse outcomes, Andreadis explained. These patients typically undergo subsequent multi-agent chemotherapy, a toxic treatment with limited success in this population, he added.

“Unfortunately, patients whose cancers relapse or don’t respond to initial therapy face a poor outlook, as only 30 to 40 percent of these patients respond to subsequent multi-agent chemotherapy and even fewer develop long-term remissions. Most patients will eventually succumb to their disease,” he said.

New therapies targeting AML-specific mutations have been developed in recent years; however, these target select patients, highlighting the need for new, widely applicable therapies, according to Andreadis.

How the Study was Conducted: In their study, Andreadis and colleagues evaluated the safety and efficacy of an investigational agent targeting a shared chemical pathway in combination with single-agent chemotherapy in patients with relapsed/refractory AML. The investigational therapy, ficlatuzumab, is a first-in-class monoclonal antibody that binds the extracellular hepatocyte growth factor (HGF) to prevent it from activating MET signaling and stimulating tumor growth. “Unlike most existing targeted cancer therapies, ficlatuzumab targets an extracellular factor instead of a cancer-specific mutation,” Andreadis noted, adding that some patients with refractory AML have higher levels of circulating HGF.

The phase I clinical trial enrolled 17 adult patients with AML that was either refractory to prior treatment or that had relapsed within 12 months of prior treatment. Patients received four doses of ficlatuzumab, administered 14 days apart, along with the chemotherapeutic cytarabine.

Results: Nine of 17 patients (53 percent) had a complete response, and four of the responding patients had no signs of minimal residual disease. Among responding patients, the progression-free survival was 31.2 months, and the overall survival was not reached. Ten patients (eight responders and two non-responders) proceeded to allogeneic hematopoietic cell transplantation; six of these patients remained in remission at the most recent follow-up.

The most common adverse event was febrile neutropenia. Serious adverse events occurred in two patients, and there was one death unrelated to the investigational therapy.

To identify molecular changes associated with treatment response, Andreadis and colleagues analyzed peripheral blood mononuclear cells collected at baseline and at several timepoints after treatment initiation. They found that ficlatuzumab treatment led to attenuated phosphorylation of MET, the receptor for HGF, thereby confirming on-target inhibition of HGF. Clinical response to ficlatuzumab treatment was associated with reduced phosphorylation of the S6 protein and increased expression of genes involved in myeloid and leukocyte activation, whereas non-responding patients were more likely to have increased expression of HGF, increased phosphorylation of S6, and expression of genes involved in protein translation, cell adhesion, and type I interferon signaling.

Author’s Comments: “The 53 percent response rate was quite striking to us since historical response rates for the standard-of-care treatment are in the 30 percent range,” noted Andreadis. “While these results need to be validated in a larger study, they suggest that ficlatuzumab in combination with single-agent chemotherapy may lead to better responses with less toxicity in patients with relapsed/refractory AML.”

“By comparing pre-treatment to post-treatment blood samples using state-of-the art single-cell mass cytometry and RNA sequencing, we observed that ficlatuzumab successfully suppressed HGF signaling, and we also identified biomarkers of treatment response and resistance,” said Wang. “This approach provided novel insight into the molecular changes that occur upon treatment, which could have clinical implications for tracking treatment response or identifying patients likely to respond.”

“Together, our findings suggest that targeting an extracellular factor in conjunction with existing cancer therapies could be an effective therapeutic strategy for AML treatment,” said Andreadis.

Study Limitations: Limitations of the study include the small sample size and its single-arm design. Andreadis and Wang noted that since the study was designed to assess safety and dosing, rather than efficacy, additional studies to validate the efficacy findings will be needed. A phase II clinical trial to evaluate ficlatuzumab plus chemotherapy has been initiated. An additional limitation was the lack of bone marrow specimens for the gene expression analyses.

Funding & Disclosures: The study was supported by the National Cancer Institute, the Damon Runyon Postdoctoral Award, the American Society for Clinical Oncology Young Investigator Award, the Department of Defense, and a Gateway for Cancer Grant. Andreadis and Wang declare no conflicts of interest.


Reference: Victoria E. Wang, Bradley W. Blaser, Ravi K. Patel, Gregory K. Behbehani, Arjun A. Rao, Blythe Durbin-Johnson, Tommy Jiang, Aaron C. Logan, Matthew Settles, Gabriel N. Mannis, Rebecca Olin, Lloyd E. Damon, Thomas G. Martin, Peter H. Sayre, Karin M. Gaensler, Emma McMahon, Michael Flanders, Vivian Weinberg, Chun J. Ye, David P. Carbone, Pamela N. Munster, Gabriela K. Fragiadakis, Frank McCormick and Charalambos Andreadis, “Inhibition of MET Signaling with Ficlatuzumab in Combination with Chemotherapy in Refractory AML: Clinical Outcomes and High-Dimensional Analysis”, Cancer Discovery, 2021. DOI: 10.1158/2643-3230.BCD-21-0055


Provided by AACR

Sensing “Junk” RNA After Chemotherapy Enhances Blood Regeneration (Biology)

Hematopoietic stem cells take advantage of RNA from pathogenic remnants integrated in the genome to replenish the blood system

Chemotherapy kills cycling blood cells thus sending signals to hematopoietic stem cells (HSCs) in the bone marrow to produce more differentiated blood cells. Scientists from the MPI of Immunobiology and Epigenetics in Freiburg reveal that during hematopoietic regeneration, RNA expressed from a part of the genome considered as “junk DNA” is used by hematopoietic stem cells to get activated and proliferate. The study published in the scientific journal Nature Cell Biology shows that these so-called transposable elements make RNA after chemotherapy and activate an immune receptor which induces inflammatory signals enhancing hematopoietic stem cell cycling and thus participating in the regeneration of the hematopoietic system.

Chemotherapy is widely used to treat cancer patients. During the treatment, chemotherapeutic agents affect various biochemical processes to kill or reduce the growth of cancer cells, which divide uncontrollably in patients. However, chemotherapy’s cell-damaging effect affects cancer cells and, in principle, many other cell types, including cycling blood cells. This puts the hematopoietic system under severe stress and pushes hematopoietic stem cells (HSCs) in the bone marrow to produce fresh cells and replenish the stable pool of differentiated blood cells in the body.

Researchers from the MPI of Immunobiology and Epigenetics, together with colleagues from the University of Freiburg, Lyon, Oxford, and St Jude Children’s Research Hospital in Memphis, now discovered that hematopoietic stem cells make use of RNA molecules from junk DNA sections to enhance their activation after chemotherapy.

Wake-up inflammation for HSC

Hematopoietic stem cells lie on the top of the hematopoietic hierarchy and give rise to most blood cells, including immune cells. Under normal conditions, HSCs kept dormant in the bone marrow to preserve their long-term self-renewal potential and prevent stem cell exhaustion. However, upon chemotherapy, they are “forced” to exit quiescence and start cycling. “Hematopoietic stem cells respond to chemotherapy by starting proliferating. We know that inflammatory signaling is pivotal for HSC activation. However, we still don’t understand completely how this happens”, says Eirini Trompouki, group leader at the MPI of Immunobiology and Epigenetics in Freiburg.

A link between chemotherapy-induced inflammation and junk RNA

Interestingly, she and her team observed that other RNA molecules besides the RNAs of “classic” coding genes are transcribed in HSCs after chemotherapy. A part of these RNAs stems from active or inactive transposable elements. Transposable elements are remnants of pathogens such as viruses or bacteria that have been integrated into the genome through millions of years of evolution. Researchers often considered these extensive strands of genetic material that dominate the human and mouse genome by more than one-third but seem to lack specific functions as “junk DNA.”

Once the team noticed that RNA from these elements is increased after chemotherapy, the question then became: “Is there a link between transposable element RNA and the increased inflammatory signals observed after chemotherapy?” explains Thomas Clapes, lead author in the study. Indeed, HSCs express some receptors that could induce inflammation, but they are primarily associated with immune cells, and their role is to sense viral RNA. “We hypothesized that these receptors could also bind to transposable element RNA,” says Aikaterini Polyzou. The data of the scientists show that transposable element RNA can bind to the immune receptor MDA5 and trigger an inflammatory response that results in HSCs exiting dormancy and starting to proliferate. “Without these interactions, HSC activation becomes slower and less efficient. This indicates that RNA sensing is probably not necessary for hematopoietic regeneration but helps to enhance blood regeneration after chemotherapy,” say Thomas Clapes, Aikaterini Polyzou, and Pia Prater.

Mechanism or adaptation?

These findings help to better understand the molecular underpinnings of hematopoietic regeneration, especially after chemotherapy. However, the results also pinpoint that transposable element RNA is used by the cells during developmental transitions. The transition of a cell from an inactive-quiescent to an active proliferative state means a massive reorganization of the genome. For example, the cell needs to switch off genes responsible for the energy-saving mode and turns on genes essential for increased metabolism or cell cycling. “It is interesting to think that cells make use of transposable elements or other repetitive RNAs to finetune and adapt whenever they need to change their state, for example after stress, like chemotherapy or even after physiological stress signals like development or aging,” says Eirini Trompouki. The scientists assume that the usage of RNA is a way for the cell to sense and buffer transcription. “We have many more things to find out to be able to understand if RNA sensing is an evolutionary adaptation used in cases of high cellular plasticity to finetune cell fate decisions,” says Eirini Trompouki.

Featured image: Under homeostatic conditions HSCs are quiescent in the bone marrow. Upon chemotherapy transposable element (TE) RNA is increased and activates the innate immune receptor MDA5. This leads to induction of inflammatory signals that are aiding HSCs to exit quiescence and start proliferating in order to replenish the differentiated blood cells that were eliminated by chemotherapy. © Created with BioRender.com


Reference:

Clapes T, Polyzou A, Prater P, Sagar, Morales-Hernández A, Galvao Ferrarini M, Kehrer N, Lefkopoulos S, Bergo V, Hummel B, Obier N, Maticzka D, Bridgeman A, Herman JS, Ilik I, Klaeylé L, Rehwinkel J, McKinney-Freeman S, Backofen R, Akhtar A, Cabezas-Wallscheid N, Sawarkar R, Rebollo R, Grün D and Trompouki E (2021), Chemotherapy-induced transposable elements activate MDA5 to enhance haematopoietic regeneration, Nature Cell Biology 12 July 2021 DOI: 10.1038/s41556-021-00707-9


Provided by MPIIE

Tumor Cell PD-L1 May Mediate Sensitivity To Chemotherapy in Colorectal Cancer Treatment (Medicine)

Data in a study by Mayo Clinic Cancer Center researchers indicates that the level of tumor cell PD-L1, a protein that acts as a brake to keep the body’s immune responses under control, may be an important factor for sensitivity to chemotherapy in colorectal cancer treatment. The study was published Friday, July 2, in Oncogene.

“We have identified a mechanism by which absent or low levels of tumor cell PD-L1, which is commonly found in solid tumors, can confer resistance to chemotherapy in colorectal cancer,” says Frank Sinicrope, M.D., a Mayo Clinic medical oncologist and gastroenterologist, and the study’s author.

PD-L1 is a protein that is increased on some human cancer cells and is a target for immunotherapy, but its role in response to chemotherapy is poorly understood.

“Our study found that the loss of PD-L1 in tumor cells was shown to enhance JNK signaling that modifies a protein called BIM, resulting in its inactivation such that it cannot mediate the killing of cancer cells,” says Dr. Sinicrope. He says targeting JNK may be a promising strategy to overcome drug resistance in cancer cells with low or absent tumor cell PD-L1 expression, which is typical in most colorectal cancers.

“Our results identify an important mechanism by which low or absent levels of PD-L1 protien may contribute to lack of response to chemotherapy,” says Dr. Sinicrope. He says the findings suggests a potential new strategy to target the JNK pathway, thereby sensitizing colon cancer cells to chemotherapy.

“We have identified an important role of PD-L1 in colon cancer cells that is independent of it serving as a target for cancer immunotherapy,” says Dr. Sinicrope. “Our findings demonstrate that frequently identified low or absent PD-L1 levels in human colorectal cancer cells can be a cause of resistance to chemotherapy.” He says the study findings indicate that the mechanism of this effect is mediated by enhanced JNK signaling, and inhibiting this signaling may be a promising strategy to overcome resistance to drug therapy in colorectal cancer treatment.


Reference: Sun, L., Patai, Á.V., Hogenson, T.L. et al. Irreversible JNK blockade overcomes PD-L1-mediated resistance to chemotherapy in colorectal cancer. Oncogene (2021). https://doi.org/10.1038/s41388-021-01910-6


Provided by Mayo Clinic

Platinum-chemotherapy Can Enhance the Treatment Resistance of Ovarian Cancer Cells (Medicine)

Researchers from Karolinska Institutet have discovered how platinum-chemotherapy can enhance the treatment resistance of ovarian cancer cells, by progressively changing the cancer cell-intrinsic adhesion signaling and cell-surrounding microenvironment.

Platinum chemotherapy is standard treatment in ovarian cancers, but treatment resistance commonly develops. The extracellular matrix (ECM)-derived biochemical and mechanical cues in the tumor microenvironment are known to contribute to the ability of cancer cells to metastasize and resist treatment. However, how the dynamic communication between the cancer cells and the ECM is affected by, or influences the disease progression and chemotherapy, have remained elusive.

A new study led by Kaisa Lehti, researcher at the Department of Microbiology, Tumor and Cell Biology at KI, and published in Nature Communications, shows that the ECM microenvironment is modulated in metastasis and following chemotherapy. Changes in the ECM proteins variably altered the cell death response of the tumour cells.

“Particularly in the most aggressive solid tumor tissues, cancer cells are surrounded by a prominent fibrotic network of proteins like collagens, known as the extracellular matrix (ECM) and also defined as the matrisome when considered with various associated factors including cytokines and chemokines. The ECM/matrisome is produced largely by stromal cells, but sensed and remodeled collectively by the cancer cells and the cells of the fibrotic tumor stroma. In tumor cells, specific ECM signaling in stiff microenvironment critically increased their resistance against platinum-mediated, apoptosis-inducing DNA damage”, Kaisa Lehti explains.

Read the full article in Nature Communications

The study included key clinical collaboration with University of Turku and Turku University Hospital as well as Karolinska University Hospital and was completed in collaboration with Norwegian University of Science and Technology, NTNU. It was funded by the KI Strategic Research Program in Cancer (KI Cancer Research), the Swedish Cancer Society, the Swedish Research Council, Sigrid Juselius Foundation, the Finnish Cancer Foundation, Orion Research Foundation, K. Albin Johanssons Foundation, Emil Aaltonen Foundation, the European Union’s Horizon 2020 research and innovation program (under grant agreement HERCULES) as well as the Doctoral Program in Integrative Life Sciences, University of Helsinki.

Featured image: Ovarian cancer cells Photo: N/A


Provided by Karolinska Institute

CNIO Researchers Discover A Protein That Facilitates DNA Repair May Potentiate Chemotherapy (Biology)

The PrimPol protein helps the cell to survive the damage caused by chemotherapy; the researchers want to make tumor cells more sensitive to cancer treatments by repressing PrimPol

Chemotherapy kills tumour cells by causing damage to them. One of the most effective ways of causing damage is to prevent the two DNA strands from separating so that the cellular machinery cannot read the instructions written in the genes. But sometimes, the cell manages to repair the damage and survive, evading the effect of chemotherapy. CNIO researchers have found out how the cell does that and plan to use this knowledge to enhance cancer treatments.

The key lies in a peculiar protein called PrimPol, as explained in a publication in The EMBO Journal by the CNIO’s DNA Replication Group, led by Juan Méndez.

The DNA molecule harbours the genes that direct the life of the cell and, by extension, the life of the whole organism. It consists of two intertwined strands, the famous double helix. For the instructions written in the genes to be read by the cellular machinery, the two strands of DNA must be pulled apart and put back together again, like a zipper that opens and closes. If this does not happen, the cell cannot function and, of course, cannot replicate.

That is why lesions that prevent DNA strands from separating are among the most serious that a cell can suffer. They are called interstrand cross-links (ICLs). ICL lesions can appear naturally, as a result of cell metabolism, or as a consequence of certain toxins, such as chemotherapeutic drugs. Cisplatin, used in the treatment of among others ovarian and lung cancers, kills tumour cells by inducing ICL lesions.

A ‘staple’ that holds the double helix together

As Méndez explains, “The ICL is a chemical bond between the two strands, a kind of staple that prevents them from separating. If the cell tries to divide, the chromosomes end up breaking.”

The cell, however, knows how to repair these lesions, which in fact only become lethal when their frequency is very high. In the paper now published in The EMBO Journal, the CNIO group reveals that the cell achieves this in part thanks to PrimPol.

Binding of PrimPol to ICL lesions in DNA. PrimPol protein (red) is distributed between the nucleus (blue) and cytoplasm of osteosarcoma cells (left). In the presence of ICL lesions, PrimPol quickly binds to damaged DNA to facilitate its repair (right). © CNIO

PrimPol belongs to a family of proteins called “primases” that appeared very early in the evolution of life and is still present today in a great many species, which indicates its importance for the functioning of organisms. In 2013, Juan Méndez and Luis Blanco, from the Centro de Biología Molecular Severo Ochoa (CSIC), discovered why PrimPol is so important: it allows the cellular machinery to use the instructions written in the DNA even when it contains an error. In other words, PrimPol makes the cell more resilient by helping it to survive when its DNA is damaged.

PrimPol helps to keep reading the DNA

Usually, DNA-copying proteins are blocked when they detect defects in the double helix, and if the blockage persists for too long, the cell will die. But PrimPol enables the reading of the DNA to continue after the error, like keeping on reading a text after skipping a misspelt or misunderstood word. “PrimPol,” explains Méndez “offers ‘an immediate solution’ to bypass the blockage, giving the cell a chance to repair the error in the DNA at a later time.”

The new study focuses on PrimPol’s function when the error is an ICL lesion. The researchers found that PrimPol is required for the DNA copying phase that precedes the repair of the staple in the DNA strands. Thanks to the intervention of this enzyme, the cell not only survives ICL lesions but also mobilises the machinery responsible for repairing them.

Repressing PrimPol to potentiate chemotherapy

It is a basic finding, but “with very interesting clinical implications,” says Méndez, because “by facilitating the repair of ICLs, PrimPol is interfering with the effectiveness of chemotherapy.”

That suggests that if PrimPol were absent, the tumour cell would be more sensitive to chemotherapy. The authors, therefore, believe that the new results “open the possibility of targeting PrimPol to enhance the therapeutic effects of molecules that produce ICL lesions,” they write in The EMBO Journal.

In another recent study in which Méndez participated together with researchers from Washington University (St Louis, USA), it was found that ovarian tumour cells produce more PrimPol to tolerate DNA damage caused by cisplatin-based chemotherapy.

“If we can repress PrimPol function in these cells, we could improve the efficiency of chemotherapy,” Méndez points out. To this end, his team is working together with CNIO’s Experimental Therapeutics Programme to identify specific PrimPol inhibitors.

Fanconi anaemia

The new study is also of interest for Fanconi anaemia, a rare and severe disease. The CNIO researchers show that PrimPol facilitates the repair of ICL lesions by a family of proteins called FANC. And genetic defects that reduce the activity of these proteins cause Fanconi anaemia.

“Patients with Fanconi anaemia have very few therapeutic options, but very promising results are beginning to be obtained with gene therapy,” says Méndez. “Any advances that lead to a better understanding of the ICL repair pathways may prove useful in the near future.”

The experimental work was carried out by three PhD students supervised by Méndez: Daniel González, Elena Blanco and Patricia Ubieto. Luis Blanco, a CSIC scientist, Massimo Lopes, a scientist at the University of Zurich (Switzerland), and the CNIO Proteomics Core Unit also participated.

The research has been funded by the Spanish Ministry of Science and Innovation, the National Institute of Health Carlos III, the European Regional Development Fund., the Swiss National Science Foundation and the European Research Council.

The study, “PrimPol-mediated repriming facilitates replication traverse of DNA interstrand crosslinks”, EMBO J (2021)e106355. https://doi.org/10.15252/embj.2020106355

Featured image: The director of the study, Juan Méndez, in the center, together with the researchers Elena Blanco-Romero, on the left, and Patricia Ubieto-Capella, on the right. © CNIO


Provided by CNIO

Lung Cancer’s Resistance to Chemotherapy Reveals New Treatment Approach (Medicine)

Garvan researchers uncover a mechanism behind lung cancer’s block to effective treatment.

New research at the Garvan Institute of Medical Research and ANZAC Research Institute has uncovered a mechanism that helps lung cancer cells resist standard chemotherapies.

A team led by Associate Professor David Croucher and Associate Professor Andrew Burgess found that individual lung adenocarcinoma cells, the most common form of lung cancer, were more likely to be resistant to platinum-based therapies when the treatment was administered during a certain stage of the cell life cycle.

The findings of the proof-of-principle study, recently published in the journal eLife, help explain why survival rates for lung cancer are so low and could prove to be an important piece in the puzzle of designing more effective treatments that improve patient outcomes, says co-senior author Associate Professor Croucher.

“Understanding the genetic factors that influence resistance to chemotherapy is hugely important to improving patient outcomes,” says Associate Professor Croucher, who heads the Network Biology Lab at the Garvan Institute.

“But this study has shown a non-genetic mechanism – essentially the replication of DNA which occurs as cancer cells rapidly grow and divide – that allows the cancer cells to be resistant to treatment. Having identified this mechanism, we now need to find ways to overcome it, because our standard approaches for targeted therapies do not take it into account,” says co-senior author Associate Professor Burgess, from the ANZAC Research Institute and the University of Sydney.

Current therapies fall short

Lung cancer is the leading cause of cancer-related deaths, claiming more than 1.5 million lives around the world each year. Better therapies for treating advanced stages of the disease are urgently needed as tumours are often diagnosed only once they have progressed to late stages of disease.

“Platinum-based chemotherapies, such as the drug cisplatin, have been used to treat lung cancer for more than 40 years despite only a small portion of patients responding positively to the treatment. The vast majority (70%) are resistant to these common therapies,” says Associate Professor Burgess.

To better understand what underpins adenocarcinoma drug resistance, the researchers investigated how adenocarcinoma cells responded to treatment during different stages of their life cycle, which all cells go through as they grow and divide to produce new cells.

Using RNA sequencing and fluorescent biosensors to track how the cells survived over time, the team administered cisplatin to the cancer cells in tissue culture using a method that closely simulates drug metabolism in patients.

“We identified that adenocarcinoma cells that were in the early S phase of their life cycle were better able to grow and divide after treatment than cells at other stages of growth,” says first author Dr Alvaro Gonzalez Rajal.

“These findings correlated with reduced DNA damage over multiple generations of these cells, where cells that had been in other stages of growth when cisplatin was administered maintained higher levels of DNA damage.”

Dr Alvaro Gonzalez Rajal
Dr Alvaro Gonzalez Rajal © Garvan

Path towards combination therapies

Associate Professor Croucher says that early S phase cancer cells are at the ideal stage of their life cycle to repair the damage caused by platinum-based chemotherapy because they are rapidly duplicating their DNA in preparation for cell division.

“We’ve shown that cells that are just starting to replicate their DNA are more resistant to this treatment, because the chemotherapy destroys the cancer cells by damaging the DNA. As the cells in early S phase are at a point where they’re actively replicating their DNA, they are primed to recognise and fix the damage and survive the treatment,” says Associate Professor Burgess.

“Encouragingly, further experiments have demonstrated that cells treated with PARP/RAD51 inhibitors, which prevent cancer cells from repairing themselves, also maintained damage similar to cells at other stages of the cell cycle.”

“This research demonstrates a path forward in developing treatments that improve on current standard therapies, by preventing resistance to treatment. If we can find a way to target this mechanism for resistance in patients, then we could hopefully increase the effectiveness of platinum-based therapies and drastically improve the outcomes for lung cancer patients,” says Associate Professor Croucher.

This research was supported by the Helen Guest Fellowship, the Cancer Institute NSW, National Breast Cancer Foundation, and Tour de Cure, with thanks to the ANZAC Microscopy and Flow Facility, the Sydney Informatics Hub, and the University of Sydney.

Featured image: Associate Professor David Croucher © Garvan Institute of Medical Research


Provided by Garvan

Why Some Children Develop Secondary Leukaemia After Neuroblastoma Treatment? (Neuroscience)

New study used whole genome sequencing to gain further understanding of why some children develop secondary leukaemia after neuroblastoma treatment

Scientists from the Wellcome Sanger Institute and the University of Cambridge found that in children with neuroblastoma – a cancer of immature nerve cells – treatment with platinum chemotherapy caused changes to the genome that could then cause leukaemia in some children later on.

The findings, published 27th May 2021 in Blood could lead to an ability to identify which children are more likely to develop the secondary cancer. This in turn could lead to changes in their treatment plan to either avoid these risks or take measures to prepare.

Secondary blood cancer is a challenging complication of childhood neuroblastoma cancer treatment. Every year around 100 children in the UK are diagnosed with neuroblastoma*, and those who had high-risk treatment are at an increased risk of developing secondary blood cancer – leukaemia – after neuroblastoma treatment.

Neuroblasoma often requires intense treatment including several chemotherapy drugs. These powerful drugs kill cancer cells very effectively but unfortunately also have side effects, including damaging the DNA of healthy cells, including bone marrow cells. In up to 7 per cent of childhood neuroblastoma survivors, damaged bone marrow cells go on to develop into secondary leukaemia.

In this new study, researchers from the Wellcome Sanger Institute and the University of Cambridge sequenced the whole genomes of bone marrow and blood samples of two children who both had developed blood cancer following high-risk neuroblastoma treatment.  They discovered that the seeds of secondary leukaemia were sown by neuroblastoma chemotherapy right at the beginning of treatment.

“We have been able to unravel the root of secondary leukaemia in these children which seems to lie in the early stages of neuroblastoma treatment. We hope to further investigate this to try to identify children at higher risk, and to inform a more tailored treatment plan to reduce the risk of secondary leukaemia.”

Dr Sam Behjati,co-lead author and group leader at the Wellcome Sanger Institute

The team found that in both patients the leukaemia had mutations that were caused by neuroblastoma chemotherapy. A wider analysis of 17 children treated for a variety of cancers then identified another child who had undergone neuroblastoma treatment and had developed pre-leukaemia seeds. In the future, it could be possible to identify the children who have a higher risk of developing secondary leukaemia by sequencing their genome and highlighting any genetic drivers that could be pre-cursors for blood cancer.

“This research would not have been possible without the contributions of the patients and their families, and we are indebted to them for their participation in this study. Understanding the reason why some childhood cancer survivors go on to develop secondary blood cancer is crucial if we are to find a way to help protect against this devastating complication.”

— Dr Grace Collord,joint first author from the Wellcome Sanger Institute

“Neuroblastoma can be an aggressive disease that requires intense chemotherapy treatment. Occasionally this chemotherapy can cause serious adverse effects such as leukaemia. So these findings are important to inform possible strategies for monitoring for secondary cancer and tailoring individual treatment plans. However, I should stress that it remains vital that children with high risk neuroblastoma continue to receive intense treatment for their cancer.”

Professor John Anderson of Great Ormond Street Hospital, who contributed to this study

This study included patients, research nursing teams, and laboratory staff from Addenbrooke’s Cambridge University Hospital and Great Ormond Street Hospital (London).

Publication:

Tim H.H. Coorens, Grace Collord and Sam Behjati, et al. (2021) Clonal hematopoiesis and therapy-related myeloid neoplasms following neuroblastoma treatment. Blood. DOI:10.1182/blood.2020010150

Funding:

This project is supported by Wellcome and St. Baldrick’s Foundation. Further support was provided by NIHR and Great Ormond Street Hospital Children’s Charity.

Featured image credit: Adobe stock


Provided by Wellcome Sanger Institute

Cell Mechanics Research is Making Chemotherapy Friendlier (Medicine)

Malignant tumour cells undergo mechanical deformation more easily than normal cells, allowing them to migrate throughout the body. The mechanical properties of prostate cancer cells treated with the most commonly used anti-cancer drugs have been investigated at the Institute of Nuclear Physics of the Polish Academy of Sciences in Cracow. According to the researchers, current drugs can be used more effectively and at lower doses.

In cancer, a key factor contributing to the formation of metastasis is the ability of the neoplastic cells to undergo mechanical deformation. At the Institute of Nuclear Physics of the Polish Academy of Sciences (IFJ PAN) in Cracow, research on the mechanical properties of cells has been conducted for a quarter of a century. The latest study, carried out in cooperation with the Department of Medical Biochemistry of the Jagiellonian University Medical College, concerned several drugs currently used in prostate cancer chemotherapy, and specifically their impact on the mechanical properties of cancer cells. The results are optimistic: everything indicates that the doses of some drugs can be reduced without the risk of reducing their effectiveness.

Chemotherapy is an extremely brutal attack not only on the patient’s cancer cells but on all the cells in the body. By using it, doctors hope that the more sensitive tumour cells will die before the healthy ones begin to die. In this situation, it is crucial to know how to choose the optimal drug in a given case and how to determine its minimum dose, which on the one hand will guarantee the effectiveness of the treatment and on the other hand will minimize the adverse effects of the therapy.

As early as 1999, physicists from the IFJ PAN showed that cancer cells deform mechanically more easily. In practice, this fact means that they can squeeze through the narrow vessels of the circulatory and/or lymphatic systems with greater efficiency.

“The mechanical properties of a cell are determined by elements of its cytoskeleton such as the microtubules we examine, built of tubulin (a protein), actin filaments and intermediate filaments made of proteins such as keratin or vimentin,” says Prof. Malgorzata Lekka from the Department of Biophysical Microstructures IFJ PAN and adds: “Biomechanical measurements of cells are carried out using an atomic force microscope. Depending on the needs, we can press the probe more or less onto the cell, and in this way we obtain a mechanical response coming from structures lying either at its surface, i.e. at the cell membrane, or deeper, even at the cell nucleus. However, in order to obtain information about the effects of a drug, we must evaluate what contribution each type of cytoskeleton fibre makes to the mechanical properties of the cell.”

In the currently reported results, the Cracow-based physicists presented experiments using the commercially available DU145 human prostate cancer cell line. This line was chosen for its drug resistance. Undergoing long-term drug exposure, these cells become resistant to the drugs over time and not only do not die but even begin to divide.

“We focused on the effects of three commonly used drugs: vinflunine, colchicine and docetaxel. They all act on the microtubules, which is desirable since these fibres are essential for cell division. Docetaxel stabilizes the microtubules and therefore also increases the rigidity of the tumour cells and makes it difficult for them to migrate throughout the body. The other two drugs destabilize the microtubules, so cancer cells can migrate, but due to the disturbed functions of the cytoskeleton, they are unable to divide,” says PhD student Andrzej Kubiak, the first author of the article published in the prestigious Nanoscale.

PhD student Andrzej Kubiak at the atomic force microscope. (Source: IFJ PAN)

The researchers from Cracow analysed the viability and mechanical properties of cells 24, 48 and 72 hours after drug treatment, and it turned out that the greatest changes were observed three days after drug exposure. This allowed them to determine two concentrations of drugs: one higher, which destroyed cells, and one lower, at which although cells survived, their mechanical properties were found to be altered. For obvious reasons, what happened to the cells in the latter case was of particular interest. The precise interpretation of some of the results required several tools, such as a confocal microscope and flow cytometry. Their use was possible thanks to cooperation with the Institute of Pharmacology of the Polish Academy of Sciences in Cracow, the Department of Cell Biology at the Faculty of Biochemistry, Biophysics and Biotechnology of the Jagiellonian University and the University of Milan (Department of Physics, Universita degli Studi di Milano).

“It has been known for some time that when microtubules are damaged, some of their functions are taken over by actin filaments. The combination of measurements of the mechanical properties of cells with images from confocal and fluorescence microscopes allowed us to observe this effect. We were able to accurately determine the areas in the cell affected by a given drug and understand how its impact changes over time,” emphasised PhD student Kubiak.

Practical conclusions can be drawn from the research of the Cracow physicists. For example, the effect of vinflunine is clearly visible in the nuclear region but is compensated by the actin filaments. As a result, the cell remains rigid enough to continue to multiply. On the other hand, 48 hours after the administration of the drug, the effects of docetaxel are most visible, mainly at the cell periphery. This fact also alerts us to the increased role of actin filaments and means that the therapy should be supported with a drug that acts on these filaments.

“Until now, there has been little research into the effectiveness of low concentrations of anti-cancer drugs. We show that the issue is really worth taking an interest in. For if we understand the mechanisms of action of individual drugs, we can maintain – and sometimes even increase – their current effectiveness while at the same time reducing the side effects of chemotherapy. In this way, chemotherapy can become more patient-friendly, which should affect not only the patient’s physical health but also their mental attitude which is so necessary in the fight against cancer,” concludes Prof. Lekka.

Featured image: Element with a sampling probe (highlighted) in the atomic force microscope (AFM) at the Spectroscopic Imaging Laboratory of the Institute of Nuclear Physics, Polish Academy of Sciences. (Source: IFJ PAN)


Scientific papers:

“Stiffening of DU145 prostate cancer cells driven by actin filaments – microtubule crosstalk conferring resistance to microtubule-targeting drugs”,
A. Kubiak, M. Chighizola, C. Schulte, N. Bryniarska, J. Wesołowska, M. Pudełek, M. Lasota, D. Ryszawy, A. Basta-Kaim, P. Laidler, A. Podestà, M. Lekka;
Nanoscale, 2021, 13, 6212;
DOI: https://doi.org/10.1039/D0NR06464E


Provided by IFJ