Category: Cancer

Categories : CancerTags : Leave a comment

How to Stop Melanoma’s Incredibly Swift Evasion of Treatment

On By ModernMedia
Melanoma Cells. Credit: National Cancer Institute

Researchers have uncovered a stealth survival strategy that melanoma cells use to evade targeted therapy, offering a promising new approach to improving treatment outcomes.

The study, published in Cell Systems and conducted by researchers at the Institute for Systems Biology (ISB) and Massachusetts Institute of Technology (MIT) identifies a non-genetic, reversible adaptation mechanism that allows melanoma cells to survive treatment with BRAF inhibitors. By identifying and blocking this early response, researchers proposed a combination therapy that could delay resistance and enhance the effectiveness of existing treatments.

Cracking the Code of Melanoma’s Drug Escape

Melanoma, the deadliest form of skin cancer, is often driven by mutations in the BRAF gene, which fuels uncontrolled tumor growth. While BRAF inhibitors (such as vemurafenib) initially halt tumor growth, many tumors quickly adapt and survive treatment, leading to therapy failure.

Unlike traditional resistance driven by genetic mutations, this study uncovers an early, dynamic adaptation process that occurs within hours to days of drug treatment – long before genetic resistance takes hold. Surprisingly, this process does not rely on reactivating the BRAF-ERK pathway, which is the usual resistance mechanism.

Using cutting-edge mass spectrometry-based phosphoproteomics and deep transcriptomics analyses, researchers mapped the molecular shifts in melanoma cells over minutes, hours, and days of BRAF inhibitor treatment.

“We found that while the BRAF-ERK signaling pathway was quickly and durably suppressed, cancer cells did not rely on reactivating ERK to survive. Instead, they triggered an alternative SRC family kinase (SFK) signaling pathway, which promoted cell survival and eventual recovery,” said Chunmei Liu, PhD, a bioinformatics scientist at ISB and co-first author of the paper.

Turning a Weakness Into a Target

A key discovery in this study came when researchers linked SFK activation to reactive oxygen species (ROS), a cellular stress response that builds up under BRAF inhibition. As ROS levels surged, SFK activity spiked, helping melanoma cells withstand treatment. However, this adaptation was reversible – when treatment was removed, cells returned to their original state.

Recognizing this Achilles’ heel, the team tested a combination approach: pairing BRAF inhibitors with the SFK inhibitor dasatinib.

“By adding dasatinib, we blocked this adaptive escape mechanism, significantly reducing melanoma cell survival and stabilising tumours in animal models,” said ISB Associate Professor Wei Wei, PhD, co-corresponding author.

Importantly, SFK inhibition alone had little effect on melanoma cells, highlighting the need for a strategic combination therapy to suppress melanoma adaptation before resistance fully develops. 

“This approach has the potential to prolong the effectiveness of BRAF inhibitors and improve patient outcomes,” said ISB President and Professor Jim Heath, PhD, co-corresponding author.

Looking Ahead: A Path to the Clinic

Beyond uncovering a key mechanism of drug adaptation, this research underscores the importance of early intervention to prevent it from happening. It also highlights ROS accumulation and SFK activation as potential biomarkers for identifying patients who may benefit from this combination therapy.

Further preclinical studies and clinical trials will be necessary to validate this combination therapy strategy and determine its potential for broader clinical use.

Source: Institute for Systems Biology

Categories : Cancer ExerciseTags : Leave a comment

Can Exercise Help Reduce Survival Disparities in Colon Cancer Survivors?

On By ModernMedia

Study indicates that higher levels of physical activity may lessen and even eliminate survival disparities.

Photo by Barbara Olsen on Pexels

Physical activity may help colon cancer survivors achieve long-term survival rates similar to those of people in the general population, according to a recent study published by Wiley online in CANCER, a peer-reviewed journal of the American Cancer Society.

Individuals with colon cancer face higher rates of premature mortality than people in the general population with matched characteristics such as age and sex. To assess whether exercise might reduce this disparity, investigators analysed data from two posttreatment trials in patients with stage 3 colon cancer, with a total of 2875 patients who self-reported physical activity after cancer surgery and chemotherapy. The researchers also examined data on a matched general population from the National Center for Health Statistics. For all participants, physical activity was based on metabolic equivalent (MET) hours per week. (Health guidelines recommend 150 minutes of moderate-intensity exercise per week, translating to approximately 8 MET-hours/week.)

In the analysis of data from the first trial (called CALGB 89803), for patients who were alive at three years after cancer treatment, those with <3.0 MET-hours/week had subsequent 3-year overall survival rates that were 17.1% lower than the matched general population, but those with ≥18.0 MET-hours/week had only 3.5% lower subsequent 3-year overall survival rates than the matched general population. In the second trial (CALGB 80702), among patients who were alive at three years, those with <3.0 and ≥18.0 MET-hours/week had subsequent 3-year overall survival rates that were 10.8% and 4.4% lower than the matched general population, respectively.

In pooled analyses of the two trials, among the 1908 patients who were alive and did not have cancer recurrence by year three, those with <3.0 and ≥18.0 MET-hours/week had subsequent 3-year overall survival rates that were 3.1% lower and 2.9% higher than the matched general population, respectively. Therefore, cancer survivors who were tumour-free by year three and regularly exercised achieved even better subsequent survival rates than those seen in the matched general population.

“This new information can help patients with colon cancer understand how factors that they can control—their physical activity levels—can have a meaningful impact on their long-term prognosis,” said lead author Justin C. Brown, PhD, of the Pennington Biomedical Research Center and the Louisiana State University Health Sciences Center. “Also, medical and public health personnel and policymakers are always seeking new ways to communicate the benefits of a healthy lifestyle. Quantifying how physical activity may enable a patient with colon cancer to have a survival experience that approximates their friends and family without cancer could be a simple but powerful piece of information that can be leveraged to help everyone understand the health benefits of physical activity.”

Source: Wiley

Categories : CancerTags : Leave a comment

Non-genetic Theories of Cancer Address Inconsistencies in Current Paradigm

On By ModernMedia

A recent essay argues for re-considering cancer as a genetic disease

3D structure of a melanoma cell derived by ion abrasion scanning electron microscopy. Credit: Sriram Subramaniam/ National Cancer Institute

It’s time for researchers to reconsider the current paradigm of cancer as a genetic disease, argued Sui Huang from the Institute for Systems Biology, USA, and colleagues in a new essay published March 18th in the open-access journal PLOS Biology.

The prevailing theory on the origin of cancer is that an otherwise normal cell accumulates genetic mutations that allow it to grow and reproduce unchecked. This paradigm has driven large-scale cancer genome sequencing projects, such as The Cancer Genome Atlas, to identify cancer-driving mutations and develop drugs designed to target aberrant proteins and pathways.

In their new essay, Huang and colleagues argue that this somatic mutation theory of cancer is unproductive. They point to inconsistencies in the sequencing data that contradict the current theory, including the fact that many cancers have no known driver mutations while some normal tissues can harbour cancer-causing mutations.

They propose a broader, more “holistic” view that embraces organismal biology and theory. Specifically, they encourage considering alternative paradigms that encompass non-genetic processes involved in tumorigenesis. For example, they explain the concepts of cancer as a result of disruptions in gene regulatory networks (Huang) — or of tissue organisation, a theory that considers the disturbance of the field generated by neighbouring cells and surrounding tissue (Soto-Sonnenschein). The authors argue that these alternative explanations will guide experiments to advance our understanding of the origins of cancer.

The authors add: “A full embrace of the idea that the origin of cancer lies beyond the realm of genetic mutations will open new vistas on cancer treatment and prevention.  Accepting that not all carcinogens are mutagens will strengthen public health policies aimed to prevent exposure to environmental non-mutagenic factors that may promote cancer, such as food additives and plastics and many other toxicants that alter tissue homeostasis.”

Provided by PLOS

Categories : Cancer Surgeries & ProceduresTags : Leave a comment

Lymph Node Transfer Reduces Lymphoedema After Breast Cancer Surgery

On By ModernMedia
Photo by Michelle Leman on Pexels

A multicentre study led from Finland has shown that lymph node transfer is a viable treatment for the swelling in the affected limb, a condition known as lymphoedema, after breast cancer surgery. Unfortunately, a drug to improve the outcomes of the transfer treatment was not shown to be effective. 

“I am becoming increasingly convinced that lymphoedema is not just a lymphatic problem, but is connected to an immunological factor,” says Plastic Surgeon and InFLAMES Flagship Researcher Pauliina Hartiala from the University of Turku in Finland.

The study by Hartiala and collaborators was published in the journal Plastic and Reconstructive Surgery.

Around one in four women with breast cancer undergo an axillary lymph node removal surgery. The surgery is performed if tests show that the cancer has spread from the breast tissue to the lymph nodes and is often followed by radiotherapy.

After the treatment, around 20–40% of women develop lymphoedema, a lymphatic drainage disorder in the affected arm. In 2022, about 2.3 million women were diagnosed with breast cancer worldwide. In men, the disease is rare.

Swelling can start years after treatment

“Lymphedema usually starts about six months after cancer surgery, but can also occur with a delay of several years after the cancer has been treated,” says Pauliina Hartiala.

In lymphedema, fluid accumulates in the tissue at first, but over time fat and firm connective tissue also begin to accumulate in the arm. Eventually, the upper limb becomes thick and clumsy. An elastic compression sleeve is used to try to control the problem by applying pressure to prevent the limb from swelling. However, the swelling can become so severe that the arm clearly interferes with everyday life, both at work and at leisure.

Lymphedema can be treated with surgical options including liposuction, lymphatic bypass procedure, or lymph node transfer. In the transfer surgery, the patient’s lymph nodes are transferred from the groin area to the armpit, or axilla, to replace the removed lymph nodes. The procedure involves extensive scar removal from the armpit.

Lymph node transfer is often performed at the same time as the breast operated on for cancer is reconstructed with a tissue flap taken from the patient’s abdomen. 

A lymph node transfer involves removing lymph nodes from the groin area and transferring them into the armpit. Image: Pauliina Hartiala

Additional benefits were expected from a growth factor

Pauliina Hartiala was one of the leaders of a multicentre study in Turku, Finland, focused on investigating whether the outcome of lymph node transfer could be improved by a growth factor, a drug called Lymfactin, that promotes growth and repair of lymphatic vessels. The study was carried out in five research centres in Finland and Sweden and builds on extensive basic research led by Finnish Professors Kari Alitalo, Seppo Ylä-Herttuala and Anne Saarikko. Lymfactin is a research product from the Finnish pharmaceutical company Herantis Pharma.

The study tested whether the growth factor could improve lymph node flap function compared to a lymph node transfer conducted without the drug. The study involved 39 women. Of these, 20 underwent a transfer procedure where the tissue flap was injected with the lymphatic growth factor before it was transferred. For the second group, the transfer was carried out by adding only saline (placebo) to the tissue flap.

“Even though the drug therapy had worked well in combination with lymph node transfer in the animal model, it did not provide sufficient additional benefit to surgery in humans,” says Pauliina Hartiala.

Although Lymfactin did not work as expected in humans, Pauliina Hartiala is pleased with the other results of the study. In both study groups, the excess arm volume reduced during follow-up. In addition, the patients treated with Lymfactin had a significantly greater reduction in skin interstitial fluid than the placebo group.

“We are the first to show, with a double-blind study, that lymph node transfer is a viable treatment for some patients with lymphoedema after breast cancer surgery. One of the results of our study was the fact that the operation significantly improved women’s quality of life, which is an important finding.”

Pauliina Hartiala works as a Plastic Surgeon at Turku University Hospital, alongside her research work. She now believes that besides a lymphatic problem, lymphedema is linked to an immunological factor. It may be one or more of the immune cells that are involved in the accumulation of connective tissue and fat in the lymphoedema.   

“If this is the case, further research will allow us to investigate whether regulating the functions of this cell population could reduce fat accumulation in the limb,” concludes Hartiala.

Source: University of Turku

Categories : Cancer General InterestTags : Leave a comment

A Right to Life: Ensuring Access to Stem Cell Transplants for SA’s Children

On By ModernMedia
Photo by Jeffrey Riley on Unsplash

Every year, hundreds of South African children courageously battle blood disorders which are treatable through stem cell transplants. Yet, while at least 250 paediatric transplants are needed annually, only 18 are performed – leading to survival rates of just 20%, compared to 80% in countries like the USA and Europe.

Ahead of Human Rights Day, Palesa Mokomele, Head of Community Engagement and Communications at DKMS Africa, highlights the urgent need for action: “Every child has the right to healthcare, which should include stem cell transplants. By working together – government, healthcare providers, and the private sector – we can remove the barriers preventing children from receiving the treatment they need.”

Overcoming Barriers to Life-Saving Transplants

Mokomele notes that while there are challenges, there are also solutions. “By addressing issues such as financial constraints, medication shortages, and limited infrastructure, we can ensure that more children receive these vital treatments. Through collaboration, we can create meaningful change.”

Addressing the Cost Challenge

One of the major hurdles in providing this life-saving treatment is the high cost of stem cell transplants, which ranges from R1 million to R1.5 million. “When a child has a matching family donor, the public healthcare system covers their transplant fully. However, for the 70% of patients who require an unrelated donor, the state covers the transplant, but not the additional costs of finding and securing a suitable donor such as tissue typing, donor searches, and stem cell procurement.,” explains Mokomele.

“Public-private partnerships, however, can ensure that all associated costs are also covered,” she points out. “Together, we can make a difference in the lives of children who need these life-saving procedures. To be effective, we must collaborate more closely and take a holistic approach.”

Building Medical Expertise

“South Africa is challenged by the lack of clinically skilled haematology nurses and clinical haematologists, but we are looking into how ways to increase capacity at this level. Training and scholarships for medical and non-medical staff in haematology and transplantation can improve the level of care provided,” says Mokomele.

She outlines some of the work of non-profit organisations like DKMS Africa in supporting knowledge transfer initiatives for healthcare professionals. “Through a combination of theoretical courses, hands-on observerships, or a hybrid of both, we aim to enhance patient outcomes. We also frequently host and participate in symposia for the medical community to exchange knowledge and explore best practices, which are essential for providing the highest quality care.”

Encouraging Donor Commitment

A strong donor registry is crucial, yet despite DKMS Africa recruiting over 100 000 potential donors, 56% of those matched decline to donate when called upon. “Becoming a donor is a powerful act – it’s a chance to give a child a second chance at life,” urges Mokomele.”

Expanding Transplant Capacity

Increasing the number of transplant beds is another crucial step. Currently, only four paediatric transplant beds are available in public transplant centres – two in the Western Cape and two in Pretoria. However, she shares encouraging news: “We are in conversations with the private sector to support the expansion of more beds in Gauteng, where the bulk of patients reside. This expansion represents a crucial step toward improving access to care.”

A Call to Action: How You Can Help

“The progress we’re seeing is promising. Together, we can ensure that no child is denied a life-saving transplant due to financial, medical, or infrastructure constraints,” concludes Mokomele. “Whether by registering as a donor, supporting fundraising efforts, or advocating for policy changes, every contribution makes a difference. With collective effort and commitment, South Africa could transform paediatric stem cell treatment – offering hope, healing, and a future to the children who need it most.”

Categories : CancerTags : Leave a comment

Prostate Cancer is Not a Death Knell, Study Shows

On By ModernMedia
Credit: Darryl Leja National Human Genome Research Institute National Institutes Of Health

Prostate cancer statistics can look scary: 34 250 U.S. deaths in 2024. 1.4 million new cases worldwide in 2022. Dr Bruce Montgomery, an oncologist at University of Washington, hopes that patients won’t see these numbers and just throw up their hands in fear or resignation.  

“Being diagnosed with prostate cancer is not a death knell,” said Montgomery, senior author of a literature and trial review that appeared in JAMA. Montgomery is the clinical director of genitourinary oncology at Fred Hutch Cancer Center and University of Washington Medical Center, and a professor of medicine and urology at the UW School of Medicine.  

He encourages patients to ask their primary-care doctor specific questions about this cancer too.  Montgomery also encourages his fellow doctors to bring up the question of prostate cancer screening with their patients. 

“Knowing whether there is prostate cancer and how risky it is can be the first step. Not every cancer needs to be treated,” he said. “Sometimes it’s safe to just watch and use active surveillance.”   

A 2024 study coauthored by UW Medicine urologist Dr Daniel Lin showed that active surveillance can be extremely safe: 0.1% of men who opted for surveillance died of prostate cancer after 10 years.  

“We need to realise that prostate cancer is not one disease,” Montgomery said. “As a provider, you need to personalise your approach to the patient you’re seeing and to the disease that they personally are dealing with.” 

For example, if a 50-year-old man develops prostate cancer that is only in the prostate, then more aggressive measures may need to be considered. However, if the disease, which can be slow-moving, develops in an 80-year-old patient, the discussion may be quite different. 

“I’ve seen men that age (80s) develop prostate cancer and they’ve opted for no therapy,” he said. “They know that treatment, such as radiation, might make them feel terrible … so they just say ‘no.’ 

You, as their physician, he noted, must respect that.  

“But if you’re 50 and have 25 to 30 years in which prostate cancer can become a bigger issue, even with the downsides, most patients should get therapy,” he said.  

For more advanced prostate cancer, the number of effective treatments developed has markedly increased, as has the survival rate of men with whose prostate cancer has spread to other parts of their bodies.  

 “Metastatic prostate cancer needs therapy and research over the past 10 to 20 years has improved and continues to improve survival substantially,” he said. “Knowing who needs treatment, which treatment to use and when is both an art and a science.” 

The article covered facts that men and their doctors should know, including: 

  • Approximately 1.5 million new cases of prostate cancer are diagnosed annually worldwide. Approximately 75% of cases are first detected when the cancer is still localised to the prostate. This early detection was associated with a five-year survival rate of nearly 100%.   
  • Management includes active surveillance, prostatectomy surgical removal of the prostate, or radiation therapy, depending on risk of progression. 
  • Approximately 10% of cases are diagnosed after the cancer has spread. This stage of prostate cancer   has a five-year survival rate of 37%.   
  • The most common prostate cancer is adenocarcinoma, a type that starts in gland cells, and the median age at diagnosis is 67 years.  
  • More than 50% of prostate cancer risk is attributable to genetic factors and older age.  

Prostate cancer came to public attention, both nationally and internationally last year, when famed local travel writer, Rick Steves, announced he had developed prostate cancer. He proclaimed last month via his X account, formerly Twitter, that after radiation and surgery at UW Medicine and Fred Hutch, he was cancer free.  

Source: University of Washington School of Medicine/UW Medicine

Categories : CancerTags : Leave a comment

Research Identifies Beneficial Genetic Changes in Regular Blood Donors

On By ModernMedia
Photo by Charliehelen Robinson on Pexels

Researchers at the Francis Crick Institute have identified genetic changes in blood stem cells from frequent blood donors that support the production of new, non-cancerous cells.

Understanding the differences in the mutations that accumulate in our blood stem cells as we age is important to understand how and why blood cancers develop and hopefully how to intervene before the onset of clinical symptoms.

As we age, stem cells in the bone marrow naturally accumulate mutations and with this, we see the emergence of clones, which are groups of blood cells that have a slightly different genetic makeup. Sometimes, specific clones can lead to blood cancers like leukaemia.

When people donate blood, stem cells in the bone marrow make new blood cells to replace the lost blood and this stress drives the selection of certain clones.

Blood donation impacts makeup of cell populations

In research published in Blood, the team at the Crick, in collaboration with scientists from the DKFZ in Heidelberg and the German Red Cross Blood Donation Centre, analysed blood samples taken from over 200 frequent donors – (three donations a year over 40 years, more than 120 times in total) – and sporadic control donors who had donated blood less than five times in total.

Samples from both groups showed a similar level of clonal diversity, but the makeup of the blood cell populations was different.

For example, both sample groups contained clones with changes to a gene called DNMT3A, which is known to be mutated in people who develop leukaemia. Interestingly, the changes to this gene observed in frequent donors were not in the areas known to be preleukaemic.

A balancing act

To understand this better, the Crick researchers edited DNMT3A in human stem cells in the lab. They induced the genetic changes associated with leukaemia and also the non-preleukaemic changes observed in the frequent donor group.

They grew these cells in two environments: one containing erythropoietin (EPO), a hormone that stimulates red blood cell production which is increased after each blood donation, and another containing inflammatory chemicals to replicate an infection.

The cells with the mutations commonly seen in frequent donors responded and grew in the environment containing EPO and failed to grow in the inflammatory environment. The opposite was seen in the cells with mutations known to be preleukaemic.

This suggests that the DNMT3A mutations observed in the frequent donors are mainly responding to the physiological blood loss associated with blood donation.

Finally, the team transplanted the human stem cells carrying the two types of mutations into mice. Some of these mice had blood removed and then were given EPO injections to mimic the stress associated with blood donation.

The cells with the frequent donor mutations grew normally in control conditions and promoted red blood cell production under stress, without cells becoming cancerous. In sharp contrast, the preleukaemic mutations drove a pronounced increase in white blood cells in both control or stress conditions.

The researchers believe that regular blood donation is one type of activity that selects for mutations that allow cells to respond well to blood loss, but does not select the preleukaemic mutations associated with blood cancer.

Interactions of genes and the environment

Dominique Bonnet, Group Leader of the Haematopoietic Stem Cell Laboratory at the Crick, and senior author, said: “Our work is a fascinating example of how our genes interact with the environment and as we age. Activities that put low levels of stress on blood cell production allow our blood stem cells to renew and we think this favours mutations that further promote stem cell growth rather than disease.

“Our sample size is quite modest, so we can’t say that blood donation definitely decreases the incidence of pre-leukaemic mutations and we will need to look at these results in much larger numbers of people. It might be that people who donate blood are more likely to be healthy if they’re eligible, and this is also reflected in their blood cell clones. But the insight it has given us into different populations of mutations and their effects is fascinating.”

Hector Huerga Encabo, postdoctoral fellow in the Haematopoietic Stem Cell Laboratory at the Crick, and first joint author with Darja Karpova from the DKFZ in Heidelberg, said: “We know more about preleukaemic mutations because we can see them when people are diagnosed with blood cancer.

“We had to look at a very specific group of people to spot subtle genetic differences which might actually be beneficial in the long-term. We’re now aiming to work out how these different types of mutations play a role in developing leukaemia or not, and whether they can be targeted therapeutically.”

Source: The Francis Crick Institute

Categories : Cancer Neurology New Compounds and TreatmentsTags :

Drug More than Doubles Survival Time for Glioblastoma Patients

On By ModernMedia
MRI scan showing brain cancer. Credit: Michelle Monje, MD, PhD, Stanford University

A drug developed at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) has been shown to extend survival for patients with glioblastoma, the most common primary brain tumour in adults.

Results of a trial led by the university and reported in Nature Communications revealed that a unique investigational drug formulation called Rhenium Obisbemeda (186RNL) more than doubled median survival and progression-free time, compared with standard median survival and progression rates, and with no dose-limiting toxic effects.

“As a disease with a pattern of recurrence, resistance to chemotherapies and difficulty to treat, glioblastoma has needed durable treatments that can directly target the tumour while sparing healthy tissue,” said lead author Andrew J. Brenner, MD, PhD, professor and chair of neuro-oncology research with Mays Cancer Center at UT Health San Antonio. “This trial provides hope, with a second trial under way and planned for completion by the end of this year.”

Brenner said that the median overall survival time for patients with glioblastoma after standard treatment fails with surgery, radiation and chemotherapy is only about 8 months. More than 90% of patients have a recurrence of the disease at its original location.

Rhenium Obisbemeda enables very high levels of a specific activity of rhenium-186 (186Re), a beta-emitting radioisotope, to be delivered by tiny liposomes, referring to artificial vesicles or sacs having at least one lipid bilayer. The researchers used a custom molecule known as BMEDA to chelate or attach 186Re and transport it into the interior of a liposome where it is irreversibly trapped.

In this trial, known as the phase 1 ReSPECT-GBM trial, scientists set out to determine the maximum tolerated dose of the drug, as well as safety, overall response rate, disease progression-free survival and overall survival.

After failing one to three therapies, 21 patients who were enrolled in the study between March 5, 2015, and April 22, 2021, were treated with the drug administered directly to the tumours using neuronavigation and convection catheters.

The researchers observed a significant improvement in survival compared with historical controls, especially in patients with the highest absorbed doses, with a median survival and progression-free time of 17 months and 6 months, respectively, for doses greater than 100Gy.

Importantly, they did not observe any dose-limiting toxic effects, with most adverse effects deemed unrelated to the study treatment.

“The combination of a novel nanoliposome radiotherapeutic delivered by convection-enhanced delivery, facilitated by neuronavigational tools, catheter design and imaging solutions, can successfully and safely provide high absorbed radiation doses to tumours with minimal toxicity and potential survival benefit,” Brenner concluded.

Source: University of Texas Health Science Center at San Antonio

Categories : CancerTags :

Scientists Upend the Current Understanding of How PARP Inhibitors Kill Cancer

On By ModernMedia
Breast cancer cells. Image by National Cancer Institute

Research by UMass Chan Medical School scientists poses a new explanation for how PARP inhibitor drugs attack and destroy BRCA1 and BRCA2 tumour cells. Published in Nature Cancer, this study illustrates how a small DNA nick – a break in one strand of the DNA – can expand into a large single-stranded DNA gap, killing BRCA mutant cancer cells, including drug-resistant breast cancer cells. These findings identify a novel vulnerability that may be a potential target for new therapeutics. 

Mutations in BRCA1 and BRCA2, tumour suppressor genes that play a crucial role in DNA repair, substantially increase the likelihood of cancer. These cancers are, however, quite sensitive to anticancer drugs such as poly (ADP-ribose) polymerase inhibitors (PARPi). When successful, these cancer treatments cause enough DNA damage to trigger cancer cell death. However, the array of different damages potentially induced by these drugs makes it difficult to pinpoint the exact cause of cell death. Additionally, PARPi resistance does occur, complicating treatment and leading to recurrent cancer.

“The conventional thinking has been that single-stranded DNA breaks from PARPi ultimately generated DNA double-strand breaks, and that was what was killing the BRCA mutant cancer cells,” said Sharon Cantor, PhD, professor of molecular, cell and cancer biology. “Yet, there wasn’t much in the literature that experimentally confirmed this belief. We decided to go back to the beginning and use genome engineering tools to see how these cells dealt with single-strand nicks to their DNA.” 

Using CRISPR technology, Cantor and Jenna M. Whalen, PhD, a postdoctoral researcher in the Cantor lab, introduced small, single strand breaks into several breast cancer cell lines, such as those with the BRCA1 and BRCA2 mutation, as well BRCA-proficient cells. They found that cells with BRCA1 or BRCA2 deficiency were uniquely sensitive to nicks. They also found that breast cancer cells that lose components of the complex that protects DNA from unnecessary DNA end cuts become resistant to chemotherapy drugs such as PARP inhibitors. However, restoring double strand DNA repair functions in breast cancer cells did not save the cells from dying, thus demonstrating that these repair functions are not critical for breast cancer cell survival. Instead, the cells become even more sensitive to single strand nicks, which then accumulate and form large gaps.  

“Our findings reveal that it is the resection of a nick into a single-stranded DNA gap that drives this cellular lethality,” said Whalen. “This highlights a distinct mechanism of cytotoxicity, where excessive resection, rather than failed DNA repair by homologous recombination, underpins the vulnerability of BRCA-deficient cells to nick-induced damage.” 

The findings suggest that PARPi may also work by generating nicks in BRCA1 and BRCA2 cancer cells, exploiting their inability to effectively process these lesions. For cancers that have developed PARPi-resistance, nick-inducing therapies provide a promising mechanism to bypass resistance and selectively target resection-dependent vulnerabilities.  

“Importantly, our findings suggest a path forward for treating PARPi-resistant cells that regained homologous recombination repair: to kill these cells, nicks could be induced such as through ionizing radiation,” said Cantor. “By targeting nicks in this way, therapies could effectively exploit the persistent vulnerabilities of these resistant cancer cells.”

Source: UMass Chan Medical School

Categories : Cancer GastrointestinalTags :

Low-carb Diet’s Colorectal Cancer Risk is Mediated by the Gut Microbiome

On By ModernMedia
Gut Microbiome. Credit Darryl Leja National Human Genome Research Institute National Institutes Of Health

Researchers from the University of Toronto have shown how a low-carbohydrate diet can worsen the DNA-damaging effects of some gut microbes to cause colorectal cancer.

The study, published in the journal Nature Microbiology, compared the effects of three different diets: normal, low-carb, or Western-style with high fat and high sugar, each in combination with specific gut bacteria on colorectal cancer development in mice.

They found that a unique strain of E. coli bacteria, when paired with a diet low in carbs and soluble fibre, drives the growth of polyps in the colon, which can be a precursor to cancer.

“Colorectal cancer has always been thought of as being caused by a number of different factors including diet, gut microbiome, environment and genetics,” says senior author Alberto Martin, a professor of immunology at U of T’.

“Our question was, does diet influence the ability of specific bacteria to cause cancer?”

To answer this question, the researchers, led by postdoctoral fellow Bhupesh Thakur, examined mice that were colonized with one of three bacterial species that had been previously linked to colorectal cancer and fed either a normal, low-carb or Western-style diet.

Only one combination, a low-carb diet paired with a strain of E. coli that produces the DNA-damaging compound colibactin, led to the development of colorectal cancer.

The researchers found that a diet deficient in fibre increased inflammation in the gut and altered the community of microbes that typically reside there, creating an environment that allowed the colibactin-producing E. coli to thrive.

They also showed that the mice fed a low-carb diet had a thinner layer of mucus separating the gut microbes from the colon epithelial cells. The mucus layer acts as a protective shield between the bacteria in the gut and the cells underneath. With a weakened barrier, more colibactin could reach the colon cells to cause genetic damage and drive tumour growth. These effects were especially strong in mice with genetic mutations in the mismatch repair pathway that hindered their ability to fix damaged DNA.

While both Thakur and Martin emphasize the need to confirm these findings in humans, they are also excited about the numerous ways in which their research can be applied to prevent cancer.

Defects in DNA mismatch repair are frequently found in colorectal cancer, which is the fourth most commonly diagnosed cancer in Canada. An estimated 15 per cent of these tumours having mutations in mismatch repair genes. Mutations in these genes also underlie Lynch syndrome, a genetic condition that significantly increases a person’s risk of developing certain cancers, including colorectal cancer.

“Can we identify which Lynch syndrome patients harbour these colibactin-producing microbes?” asks Martin. He notes that for these individuals, their findings suggest that avoiding a low-carb diet or taking a specific antibiotic treatment to get rid of the colibactin-producing bacteria could help reduce their risk of colorectal cancer.

Martin points out that a strain of E. coli called Nissle, which is commonly found in probiotics, also produces colibactin. Ongoing work in his lab is exploring whether long-term use of this probiotic is safe for people with Lynch syndrome or those who are on a low-carb diet.

Thakur is keen to follow up on an interesting result from their study showing that the addition of soluble fibre to the low-carb diet led to lower levels of the cancer-causing E. coli, less DNA damage and fewer tumours.

“We supplemented fibre and saw that it reduced the effects of the low-carb diet,” he says. “Now we are trying to find out which fibre sources are more beneficial, and which are less beneficial.”

To do this, Thakur and Martin are teaming up with Heather Armstrong, a researcher at the University of Alberta, to test whether supplementation with a soluble fibre called inulin can reduce colibactin-producing E. coli and improve gut health in high-risk individuals, like people with inflammatory bowel disease.

 “Our study highlights the potential dangers associated with long-term use of a low-carb, low-fibre diet, which is a common weight-reducing diet,” says Martin.

“More work is needed but we hope that it at least raises awareness.”

Source: University of Toronto