Tag: Medication

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Leukemia Stem Cell Diversity Drives Treatment Resistance in AML

Scientists from the German Cancer Research Center and HI-STEM have uncovered a major reason why acute myeloid leukemia (AML) frequently returns after treatment. Their findings, published in Cell Stem Cell, reveal that leukemia stem cells, the rare but critical cells that sustain the disease, exist in multiple biologically distinct forms, each with different vulnerabilities and resistance mechanisms.

The discovery helps explain why venetoclax, one of the most important targeted therapies in AML, often loses effectiveness over time. More importantly, it provides a framework for designing personalized combination therapies that could prevent relapse by targeting resistant stem cell populations before they expand.

Why AML remains difficult to cure

Acute myeloid leukemia is an aggressive blood cancer characterized by the rapid accumulation of abnormal myeloid cells in the bone marrow. Although newer targeted therapies have improved outcomes, relapse remains the central clinical challenge.

One of the most transformative advances in AML treatment has been the introduction of venetoclax, a selective inhibitor of the anti-apoptotic protein BCL-2. Combined with hypomethylating agents or low-dose chemotherapy, venetoclax has substantially improved responses, particularly in older patients who are unable to tolerate intensive chemotherapy.

Yet despite these advances, most patients eventually relapse.

Researchers have long suspected that leukemia stem cells are responsible. These rare cells possess the ability to self-renew indefinitely and survive therapeutic pressure, allowing the disease to regenerate even after apparently successful treatment.

Not one leukemia stem cell—but four

In the new study, researchers analyzed samples from more than 150 AML patients to better understand how leukemia stem cells respond to therapy.

Their findings challenge the idea that AML stem cells represent a single uniform population. Instead, the team identified at least four distinct leukemia stem cell subtypes, each resembling different developmental stages of normal blood cell formation.

This developmental identity turned out to be critically important because it determined which survival pathways the cells depended on—and therefore how sensitive they were to venetoclax.

Some stem cell subtypes were highly dependent on BCL-2 and responded well to treatment. Others relied on alternative survival programs that rendered them intrinsically less sensitive to the drug.

Cancer stem cells adapt under therapeutic pressure

One of the study’s most significant findings was that leukemia stem cells are not fixed in a single state. Instead, they can dynamically reprogram themselves in response to therapy.

Venetoclax works by blocking BCL-2, a protein that protects leukemia cells from programmed cell death. When BCL-2 is inhibited, susceptible leukemia cells undergo apoptosis.

However, the researchers found that under treatment pressure, many leukemia stem cells transition into more resistant cellular states. Rather than relying on BCL-2, these resistant cells switch to using a related survival protein known as BCL-xL.

This adaptive shift effectively allows the cells to bypass venetoclax and survive treatment.

The findings strengthen a broader principle increasingly recognized across oncology: cancer is not only genetically heterogeneous but also highly plastic. Tumor cells can alter their identity to evade therapeutic pressure, making durable treatment responses difficult to achieve with single-agent therapies.

Combination therapies may overcome resistance

The study also points toward potential strategies for overcoming this resistance.

By identifying which survival pathways individual leukemia stem cell subtypes depend on, researchers showed that resistant populations could potentially be targeted with rational drug combinations. In particular, combining venetoclax with inhibitors targeting BCL-xL emerged as a promising approach.

In mouse models transplanted with patient-derived leukemia cells, these subtype-specific combination therapies were significantly more effective than current standard approaches.

This suggests that future AML therapy may require simultaneous targeting of multiple stem cell states to prevent resistant populations from emerging during treatment.

Biomarkers could guide precision medicine in AML

Another key advance from the study was the identification of biomarkers capable of distinguishing the different leukemia stem cell subtypes.

These biomarkers could eventually enable clinicians to determine, at the time of diagnosis, which resistance mechanisms are most likely to arise in a particular patient.

“This means that in the future, it may be possible to determine at the time of diagnosis which patient will benefit most from which therapy,” said Alexander Waclawiczek, PhD, first author of the study.

Such an approach would represent a major shift away from treating AML as a largely uniform disease and toward truly individualized therapy guided by stem cell biology.

A new framework for AML treatment

The findings also reinforce the growing importance of cancer stem cell biology in therapeutic design. Rather than focusing exclusively on eliminating bulk tumor cells, future strategies may increasingly aim to eradicate the specific stem cell populations capable of regenerating disease after therapy.

“The results should help to align AML therapy in the future more closely with the biological characteristics of individual AML cases and, in particular, their leukemia stem cells, rather than treating all patients according to a similar protocol,” said Andreas Trumpp, PhD, who led the study.

The next major step will be translating these findings into clinical trials testing personalized combination therapies tailored to leukemia stem cell subtype composition.

The post Leukemia Stem Cell Diversity Drives Treatment Resistance in AML appeared first on Inside Precision Medicine.

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STAT+: Capricor Therapeutics accuses Nippon Shinyaku of slow-walking plans on Duchenne drug

Capricor Therapeutics accused Nippon Shinyaku and its U.S. subsidiary of failing to follow through on marketing plans for a Duchenne muscular dystrophy treatment, and refusing to fix a pricing glitch that was belatedly discovered in their exclusive distribution agreement.

A key issue is a “fatal flaw” in a pricing formula that would make it “economically impracticable” for the therapy to reach patients covered by Medicare, Medicaid, and private insurers, according to a lawsuit filed in a New Jersey state court on Thursday. Nippon Shinyaku and NS Pharma, the subsidiary, disclosed the problem in March 2025.

Basically, the formula ties Medicare reimbursement to the price that Capricor would charge NS Pharma, since it would be the only U.S. buyer. But as it stands, the lawsuit indicated that health care providers would get reimbursed less than they would pay to cover the cost of acquiring and administering the medicine, which is called deramiocel.

Continue to STAT+ to read the full story…

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Lymphoid Cancer Risk Linked to Long Telomeres and POT1 Mutations

Researchers at the Johns Hopkins Kimmel Cancer Center and the Telomere Clinic at Johns Hopkins have identified an inherited cancer predisposition syndrome that results in unusually long telomeres that allow lymphocytes to stay in a biologically more youthful state for extended periods, increasing the risk of lymphoid malignancies. The findings, published the journal Blood, showed that inherited loss-of-function mutations in the POT1 gene disrupt normal telomere regulation and alter the aging dynamics of immune cells. The investigators found that because of this longer cellular lifespan cancer-associated mutations are persistent and expand over time, creating favorable conditions for the development of lymphoma and related blood cancers.

“The spectrum of lymphoid cancers was striking,” said senior author Mary Armanios, MD, a professor of medicine at Johns Hopkins. “Family members developed childhood leukemia, multiple forms of lymphoma, and adult-onset chronic lymphocytic leukemia—cancers often considered biologically distinct and associated with different inherited risks. Yet within the same families, multiple lymphoid malignancies appeared across generations. Some individuals developed melanoma before lymphoma, while others developed as many as five cancers over a lifetime. The good news is the cancers tended to be slow-growing and usually curable.”

Telomeres are protective caps at the ends of chromosomes that normally shorten with age and as a result of cell division, which limits the lifespan of cells that accumulate damage. POT1, or protection of telomeres 1, normally regulates telomere length by binding single-stranded telomeric DNA and restricting telomerase-mediated elongation. The researchers said that  “POT1 binds single-stranded telomeric DNA and is essential for telomere protection, but POT1 heterozygous loss of function is permissive of telomerase elongation in the absence of a detectable DNA damage response.”

For their initial research the investigators focused on 51 people from 24 families that were know to carry mutant POT1 variants. The surveyed the participants to evaluate family cancer histories and collected biological samples to define the range of cancers associated with the mutations with the aim of examining how telomeres influenced lymphocyte aging. The data showed that among this small cohort, hematologic malignancies were the second most common cancers after melanoma, occurring in 27% of participants, with lymphoid cancers accounting for approximately three-quarters of blood malignancies found.

As a result, the researchers noted that “our data identify extended cellular longevity due to long TL as an inherited risk factor for lymphoma, explaining its syndromic association with solid tumors and, in some cases, myeloproliferative neoplasms.”

The investigators also found that telomeres responded differently that is typically observed as people aga. In those people with the POT1 mutation telomere length remained stable over time and in some cases lengthened rather than shortening with age. The findings indicated that lymphocytes retained prolonged replicative capacity, allowing cells with oncogenic mutations to survive instead of being eliminated through senescence.

To find out whether these findings extended beyond the studied families, the researchers then analyzed data from 210 adults with POT1 variants enrolled in the UK Biobank and found that people carrying pathogenic POT1 variants had an eightfold increased risk of lymphoma, and 45% developed lymphoid malignancies by age 80.

The research also examined asymptomatic POT1 mutation carriers to understand how lymphoma develops before clinical diagnosis. Among carriers without lymphoma, 12 of 20 had evidence of B-cell or T-cell clonality, a precursor state associated with lymphoma development. After age 65, all studied carriers showed detectable clonality. Sequencing and cytogenetic analyses revealed lymphoma-associated mutations in nearly all mutation carriers older than 60 years.

The study was prompted by earlier research which has shown evidence linking long telomeres to tumor development. Work in animal models had shown that long telomere length can bypass cellular senescence checkpoints and increase tumor incidence. Other  research had also found POT1 mutations in melanoma, papillary thyroid cancer, glioma, sarcoma, and chronic lymphocytic leukemia. But, the prevalence and natural history of these mutations across hematologic malignancies had remained uncertain.

The findings may influence future approaches to cancer surveillance and genetic evaluation in individuals with POT1 variants. The researchers said that ultralong lymphocyte telomere length could help identify pathogenic variants and distinguish variants of uncertain significance. They noted, however, that telomere length testing may have limitations because advanced clonality can interview with the ability to accurately measure baseline telomeres.

“Our data suggest that, for now, telomere length clinical testing should be reserved for individuals with variants in the gene that have unclear significance,” Armanios said.

The post Lymphoid Cancer Risk Linked to Long Telomeres and <i>POT1</i> Mutations appeared first on Inside Precision Medicine.

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Reduced Glaucoma Risk Connected to Migraine Medication Use

Individuals with migraines have been known to have a higher risk of glaucoma development, and a new study published in Neurology suggests that use of preventative medication for migraines may be connected with reduced instance of glaucoma development.

“Glaucoma is a leading cause of blindness, and evidence has linked migraine with an increased risk of glaucoma, with both conditions affecting the capacity of the blood vessels in the brain to alter blood flow in response to stimuli,” said the study lead, Chien-Hsiang Weng, MD, clinical associate professor at Brown University.

Weng and his team surmised that drugs that help to regulate blood vessel function to prevent migraines may also help prevent the development of glaucoma. The researchers focused on assessing the efficacy of calcitonin gene-related peptide inhibitors (CGRPi), which included six medications: erenumab, fremanezumab, galcanezumab, eptinezumab, atogepant, and rimegepant.

“Since CGRP inhibitors help regulate blood vessel contraction and inflammation in the nervous system, there has been hope that these drugs could benefit eye health in people at risk of glaucoma,” said Weng.

In this retrospective cohort study, the researchers collected data from a healthcare database including individuals who were prescribed migraine prevention drugs with at least one refill between 2018 and 2024. These individuals were tracked for three years to identify glaucoma diagnoses.

The researchers analyzed data from over 73 thousand participants, 36,822 of which were prescribed drugs from the CGRPi group to prevent migraine, and an equivalent number of people prescribed non-CGRPi drugs (including valproate, topiramate, flunarizine, candesartan, lisinopril, metoprolol, propranolol, nadolol, amitriptyline and venlafaxine). To prevent confounding the data, the researchers point out that “Crossovers were not allowed, and the non-CGRPi group included only individuals who never used CGRPi.”

Primary analysis using the Cox proportional hazards model showed that within the first three years from the first prescription of the migraine medication, 153 people (0.42%) in the CGRPi group developed glaucoma, compared to 223 people (0.61%) of those in the non-CGRPi group.

When adjusted for glaucoma risk factors including migraine frequency, history of high blood pressure, and age, individuals taking CGRPi drugs have a 25% lower risk of developing glaucoma compared with those taking the non-CGRPi drugs.

Not all CGRPi drugs showed equal effectiveness in reducing the risk of developing glaucoma. The authors specify that “only users of monoclonal antibody CGRPi show a reduced risk of glaucoma compared with non-CGRPi users (HR 0.77; 95% CI 0.61–0.98).”

Additionally, not all participants responded to the CGRPi medications equally. “The reduced risk of glaucoma associated with CGRPi is also observed in older adults, women, and those with chronic migraine or migraine without aura.”

This study presented a broad overview of the comparison of the potential effectiveness of two drug groups in preventing glaucoma. While this study shows a promising correlation between reduced risk of developing glaucoma when some individuals use specific CGRPi drugs, more directed and focused studies would be required to confirm a causative impact of CGRPi treatment reducing glaucoma risk.

“Further studies are needed to confirm these results, but the findings may help us better understand both migraine and glaucoma,” confirmed Weng.

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Broader Immune Targeting Increases Immunotherapy Benefit in Colorectal Cancer

Researchers at the Icahn School of Medicine at Mount Sinai and the Mount Sinai Tisch Cancer Center have identified a potential strategy to overcome resistance to immunotherapy in colorectal cancer (CRC) by restoring coordinated interactions between T cells and macrophages within the tumor microenvironment. The findings, published in Cell Reports Medicine, suggest that durable responses to immune checkpoint blockade (ICB) depend not only on activating T cells, but also on reestablishing communication between immune cell populations that work together to eliminate tumors. The study showed that a combination strategy targeting TREM2, LAG3, CTLA4, and PD-1 achieved up to 100% tumor clearance in mismatch repair-deficient colorectal cancer models and more than 70% clearance in mismatch repair-proficient tumors, which are typically resistant to immunotherapy.

“Our findings show that it’s not enough to simply activate the immune system,” said co-senior author Nina Bhardwaj, MD, PhD, director of immunotherapy and professor of medicine at the Icahn School of Medicine. “You also need to restore the communication between immune cells so they can work together effectively against the tumor.”

Currently, anti-PD-1 therapies improve outcomes in some patients with mismatch repair-deficient tumors, but about half of patients with advanced mismatch repair-deficient CRC and most mismatch repair-proficient colorectal cancers fail to respond. In this study, researchers searched for ways to define the immune resistance pathways that limit responses and determine which pathways would need to be targeted simultaneously to overcome immune escape and generate immune memory.

To understand the mechanisms of resistance, the team used orthotopic and patient-derived colorectal cancer models along with murine tumor models and human mismatch repair-deficient colorectal cancer spheroid cultures. The study employed single-cell transcriptomics, spatial analyses, spectral flow cytometry, machine learning, and imaging approaches to characterize immune cell populations and their interactions within tumors.

The analysis of the data identified distinct immune signatures associated with treatment response and resistance. Tumor control during anti-PD-1 therapy was associated with colocalization of MHC-positive, C1Q-positive, CXCL9-positive macrophages and TCF-positive, PRF1-positive T cells. By contrast, resistant tumors contained exhausted T cells expressing TIM3, LAG3, TIGIT, and PD-1, as well as TREM2-positive macrophages concentrated in regions that excluded T cells.

The findings provides a new understanding of effective immunotherapy responses by showing that robust checkpoint blockade activity requires coordinated interactions among multiple immune cell types and not just activation of T cells alone. Specifically, it showed that macrophage remodeling and communication between macrophages and T cells are central components of successful anti-tumor immunity.

In lab studies, the team tested several therapeutic targets individually and in combination, including PD-1, TIM3, TIGIT, LAG3, CTLA4, TREM2, and IFITM. Single-agent targeting of TIM3, TIGIT, LAG3, TREM2, or PD-1 limited tumor growth in mismatch repair-deficient colorectal cancer models, but responses improved when therapies were combined.

The most effective treatment combined blockade of PD-1, LAG3, CTLA4, and TREM2. This approach increased complete tumor elimination rates to as high as 100 percent in mismatch repair-deficient colorectal cancer models and up to 73 percent in mismatch repair-proficient models. Anti-PD-1 monotherapy achieved no complete tumor responses in the models studied.

“This study highlights that overcoming immunotherapy resistance requires more than targeting a single pathway,” said co-senior author Robert M. Samstein, MD, PhD, associate professor of radiation oncology, and immunology and immunotherapy, at the Icahn School of Medicine. “By addressing both T cell dysfunction and the suppressive tumor environment, we can begin to design more effective combination strategies that have the potential to benefit a much broader group of patients.”

The findings build on prior evidence suggesting that T cell exhaustion and suppressive myeloid cells contribute to immune resistance. Earlier research had linked TCF-positive T cells to anti-PD-1 responses in melanoma and associated IL1B-positive monocytes and TREM2-positive macrophages with resistance in CRC and other tumor models.

Importantly, the study found that in mouse models where the initial tumors had been completely eliminated after checkpoint-targeted therapy were also protected against a second tumor inoculation, indicating that the combined approach generated sustained anti-tumor immunity that could reduce recurrence risk.

“This approach effectively reprograms the tumor microenvironment,” said first author Guillaume Mestrallet, PhD, a postdoctoral researcher at Mount Sinai. “By simultaneously reinvigorating T cells and targeting suppressive macrophages, we were able to restore immune coordination and generate powerful anti-tumor responses.”

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Autism Screening Proposed for Children with Epilepsy

Children with epilepsy are up to 10 times more likely than others to also have autism, according to research that exposes the scale of the association between the two conditions.

The findings, in more than 30,000 children, stress the importance of screening for developmental concerns among those with epilepsy, so support can be delivered as early as possible.

The study, Developmental Medicine & Child Neurology, revealed that girls with autism spectrum disorder (ASD) were more likely than boys to also have epilepsy.

Higher rates of intellectual disability were also seen in children with autism who additionally had epilepsy, and they were also diagnosed with the neurodiversity at an earlier age.

“Our findings emphasize the importance of screening for autism in this population to support earlier diagnosis and timely intervention, both of which are key to improving long-term outcomes,” said senior investigator Elaine Wirrell, MD, from the Mayo Clinic.

ASD and epilepsy are complex disorders of neuronal connectivity that frequently co-occur because of shared molecular and biological mechanisms.

While the increased risk of ASD in children with epilepsy is well documented, there are gaps in knowledge around its incidence and prevalence, and risk factors for their co-occurrence.

To investigate further, Wirrell and team studied the medical records of 30,490 children in Olmsted County, Minnesota, of whom 257 (0.84%) were diagnosed with epilepsy before the age of 19 years.

They found that children with epilepsy were more likely have ASD across all three research and clinical definitions compared with other children, with this likelihood increased between six and 10-fold.

The prevalence was a corresponding 21.4% versus 3.2% using broad research criteria, 14.0% versus 1.6% across stricter research criteria, and 7.9% versus 0.7% for a clinical diagnosis.

Among children with autism, those also with epilepsy were more likely to have a lower IQ on standardized testing than those in whom epilepsy was absent (56.5% versus 15.4%). Specifically, an IQ of less than 70 was observed in 57.4% of children with co-occurring epilepsy and autism compared with only 15.4% autism alone.

Those with autism and epilepsy were also more often female than those with autism alone (38.2% versus 25.8%), and were identified with autism at a younger age, at a mean of seven years and five months versus eight years and eight months).

“These insights underscore the critical need for comprehensive and early screening protocols to better address and manage the intersection of autism and epilepsy, ensuring timely interventions and tailored support for affected individuals,” the researchers concluded.

 

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Immune Mapping Links Sex-Specific Genetics to Autoimmune Disease

The largest study to date to examine immune differences between sexes at single-cell resolution has identified over 1,000 genetic switches that operate in distinct ways when comparing immune cells from men and women. Published today in The American Journal of Human Genetics, these findings could explain why women are much more likely to be affected by autoimmune conditions than men. 

“Our findings show that the immune system needs to be studied with sex in mind,” says Seyhan Yazar, PhD, group leader of the precision immunology program at the Garvan Institute of Medical Research in Australia. “Even though we know men’s and women’s immune systems differ, many studies still overlook these differences, which can limit how well we understand disease, and in turn bias treatment options.”

Yazar’s team analyzed single-cell RNA sequencing data from over 1.25 million circulating immune cells from nearly 1,000 healthy individuals who participated in the OneK1K cohort. This Australian research program maps how individual immune cells respond to disease and pathogens to determine why some individuals respond to treatment but others don’t. 

Results revealed distinct genetic and cellular profiles between both sexes. While men were found to have a higher proportion of monocytes, women showed higher levels of B cells and regulatory T cells. In men, genetic activity seemed to focus on basic cellular maintenance processes, but in women genetic activity heavily skewed towards the activation of inflammatory pathways. 

“While this highly reactive immune profile gives females an advantage in fighting viral infections, it comes with a biological trade-off: a greater predisposition to autoimmune diseases,” says Sara Ballouz, PhD, senior lecturer at the University of New South Wales (UNSW). “On the other hand, male immune cells are less primed for inflammation, making men generally more susceptible to infections and non-reproductive cancers.”

Interestingly, most of the genetic switches found to be active in individuals of one sex but not the other were not found to be located in sex chromosomes. More than 1,000 sex-specific genetic switches were identified on autosomes, with many of them being directly linked to autoimmune conditions. 

“This is the first time we have shown that these differences occur at the genetic control level, providing a new layer of insight into human immunity,” Ballouz says. “Having shown that female-biased genes are heavily enriched in inflammatory pathways, we now have another biological rationale for why the immune system can more easily mistakenly attack the body’s own tissues in women.”

The analysis found female-specific genetic variants that affected the expression of two genes linked to systemic lupus erythematosus (SLE), an autoimmune condition that is nine times more likely to affect women than men. Although conditions like SLE are multifactorial, uncovering the contribution of genetic variants to their development is an important step forward towards better understanding disease susceptibility between sexes. 

“Our findings add strong evidence that female and male autoimmune diseases may not be the same, and the way we should treat them may not necessarily be the same,” says Yazar. “Currently, clinicians rely on a one-size-fits-all management approach for most autoimmune diseases—a more inclusive approach is needed.”

Currently, autoimmune conditions are often treated with broad immunosuppressants that reduce the activity of the entire immune system. Research is striving to move towards treatments that more precisely target each person’s unique needs, which is only possible through the identification of distinct genetic pathways driving autoimmune disease. 

“If we want to realize the potential of precision medicine, we have to understand these fundamental biological variables,” says Joseph E. Powell, PhD, director of the translational genomics program at the Garvan Institute. “Treatments need to be tailored not just to the disease, but to how a patient’s immune system operates at a baseline genetic level.”

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