First-in-class targeted microRNA therapy slows cancer tumor growth

 A new cancer therapy developed by Purdue University researchers attacks tumors by tricking cancer cells into absorbing a snippet of RNA that naturally blocks cell division. As reported in Oncogene, tumors treated with the new therapy did not increase in size over the course of a 21-day study, while untreated tumors tripled in size over the same time period. The paper is tiled "A first-in-class fully modified version of miR-34a with outstanding stability, activity, and anti-tumor efficacy."

Cancer can begin almost anywhere in the human body. It is characterized by cells that divide uncontrollably and that may be able to ignore signals to die or stop dividing, and even evade the immune system. The therapy, tested in mouse models, combines a delivery system that targets cancer cells with a specially modified version of microRNA-34a, a molecule that acts "like the brakes on a car," slowing or stopping cell division, said Andrea Kasinski, lead author and the William and Patty Miller Associate Professor of biological sciences at Purdue University.

In addition to slowing or reversing tumor growth, the targeted microRNA-34a strongly suppressed the activity of at least three genes—MET, CD44 and AXL—known to drive cancer and resistance to other cancer therapies, for at least 120 hours. The results indicate that the patent-pending therapy, the newest iteration in more than 15 years of work targeting microRNA to destroy cancer, could be effective on its own and in combination with existing drugs when used against cancers that have built drug resistance.

"When we acquired the data, I was ecstatic. I am confident that this approach is better than the current standard of treatment and that there are patients who will benefit from this," said Kasinski, a member of the Purdue Institute for Cancer Research.

MicroRNA-34a is a short double strand of ribonucleic acid—a string of ribonucleic acids attached like the teeth of a zipper along the length of a sugar-phosphate chain. The two strings of the microRNA are unevenly zipped together, with one string acting to guide a protein complex to the worksite in the cell while the other string is destroyed.

In healthy cells, microRNA-34a is abundant, but its presence is dramatically reduced in many cancer cells.

While the idea of reintroducing microRNA-34a to cancer cells appears simple, the research team had to overcome many challenges in crafting an effective therapy. Naturally occurring RNA breaks down rapidly, so to improve the durability of the therapy, the team stabilized microRNA-34a by adding several small clusters of atoms along the length of the strand.

The team modeled its modifications on an FDA-approved chemical structure that researchers at the biotechnology company Alnylam used on similar short interfering RNAs. Experiments on mouse models show the modified microRNA-34a endures for at least 120 hours after being introduced.

As a bonus, the fully modified microRNA-34a is invisible to the immune system, which would ordinarily attack double-stranded RNA introduced to the body.

To ensure the modified microRNA-34a makes it to cancer cells, the team attached the double strand to a molecule of the vitamin folate. The surfaces of all cells in our body have receptors that bind to folate and draw the vitamin into the cell, but the cells in many cancers—breast, lung, ovarian and cervical—have far more folate receptors on their cell surface than do healthy cells.

The tiny microRNA-34a and folate compound penetrates the dense tissue of tumors and binds to the folate receptor on the cell surface. It is then drawn inside in a little bag of cell membrane called a vesicle. Once inside the cell, some of the microRNA-34a is able to escape the vesicle and slows cell division.

The targeted specificity of the therapy reduces the amount of the compound that must be administered to be effective, which in turn reduces potential toxicity, side effects and cost. The team can also prepare a separate version, which targets a different cell surface receptor, for prostate cancer cells, which do not produce excessive folate receptors. Kasinski and her team are confident in the value of the most recent iteration and will prepare for clinical trials.

At Purdue, Kasinski was joined in the research by Philip S. Low, Presidential Scholar for Drug Discovery, Ralph C. Corley Distinguished Professor of Chemistry, and inventor of the FDA-approved drug Cytalux; Nadia A. Lanman, a research assistant professor; Ahmed M. Abdelaal, first author and a graduate student in Kasinski's lab; and researchers Harish Kothandaraman, Kasireddy Sudarshan, Shreyas Iyer and Ikjot S. Sohal.

Kasinski disclosed the innovation to the Purdue Innovates Office of Technology Commercialization, which has filed a patent application on the IP.

More information: A first-in-class fully modified version of miR-34a with outstanding stability, activity, and anti-tumor efficacy, Oncogene (2023).

https://medicalxpress.com/news/2023-09-first-in-class-microrna-therapy-cancer-tumor.html

Understanding, preventing and treating vascular dementia

 Dementia is a group of brain diseases that share similar symptoms, such as memory, language, orientation, and behavioral issues. Vascular dementia generally develops in the elderly, affecting between 1% and 4% of people over the age of 65, according to Alzheimer's Switzerland. It is caused by vascular lesions that disrupt the blood supply to the brain, leading to the death of neurons.

There is currently no cure for vascular dementia, and the only way to combat it is prevention by controlling risk factors such as high blood pressure, high cholesterol, diabetes and smoking. Preventive measures would become more effective with the discovery of new disease biomarkers that would enable a better identification of people at risk. And this is what the HUG and UNIGE team succeeded in by discovering the role of the CCR5 receptor in the development of vascular dementia.

A new biomarker for dementia

Now published in Alzheimer's & Dementia, the study focused on CCR5, a receptor protein linked to chemokines, chemical messengers of the immune system. The team led by Dina Zekry, Head of the division of Internal Medicine for the Aged at the HUG and Associate Professor in the Department of Rehabilitation and Geriatrics at the UNIGE Faculty of Medicine, in collaboration with the team led by Karl-Heinz Krause, a senior physician in the Department of Diagnostics and Medicine at the HUG and Full Professor in the Department of Pathology and Immunology at the UNIGE Faculty of Medicine, who were both responsible for the study.

They discovered that CCR5 plays a crucial role in brain cells response to oxidative stress, a mechanism involved in the death of neurons. They also found a link between a specific genetic variant of CCR5 and that of another protein, apolipoprotein E (ApoE), known for its role in age-related dementia.

This complex genetic association considerably increases the risk of vascular dementia. "People over the age of 80 who carry this specific genotype are eleven times more likely to develop vascular dementia," explains Benjamin Tournier, Ph.D., a biologist in the Department of Psychiatry at the HUG, and a researcher in the Department of Psychiatry at the UNIGE Faculty of Medicine and first author of the study.

This research of translational nature, a concept that aims to translate fundamental discoveries into concrete clinical applications, has made it possible to clarify the probable mechanisms of dementia through a series of experiments. The research team first highlighted the potential role of CCR5 in ischemic mechanisms by examining mouse neurons "in vitro."

They then studied variations in the CCR5 and ApoE genes in a group of 362 people (205 without dementia and 189 with dementia) who agreed to give blood samples annually for a duration of five years. These findings were then verified on another cohort in Italy (157 individuals without dementia and 620 individuals with dementia), consolidating the robustness of the discovery.

Prof Zekry emphasizes the importance of this discovery as a new target for understanding and treating age-related dementia. "This is a major advance that opens doors for the early identification of individuals at risk and for the development of targeted therapies. It offers considerable hope for our society with regard to neurocognitive diseases as a whole." New treatment strategies could also emerge from these results aiming at improving the quality of life and functionality of those affected.

More information: Benjamin B. Tournier et al, CCR5 deficiency: Decreased neuronal resilience to oxidative stress and increased risk of vascular dementia, Alzheimer's & Dementia (2023). DOI: 10.1002/alz.13392

https://medicalxpress.com/news/2023-09-perspectives-vascular-dementia.html

New genes, natural toxins offer hope for cancer patients unresponsive to chemo

 Scientists from Queen Mary University of London have discovered two new genes that cause head and neck cancer patients to be resistant to chemotherapy, and that silencing either gene can make cancer cells previously unresponsive to chemotherapy subsequently respond to it.

The two genes discovered actively 'work' in most human cancer types, meaning the findings could potentially extend to other cancers with elevated levels of the genes.

The researchers also looked through a chemical library, commonly used for drug discovery, and found two substances that could target the two genes specifically and make resistant cancer cells almost 30 times more sensitive to a common chemotherapy drug called cisplatin.

They do this by reducing the levels of the two genes and could be given alongside existing chemotherapy treatment such as cisplatin. One of these substances is a fungal toxin—Sirodesmin A—and the other—Carfilzomib—comes from a bacterium. This shows that there may be existing drugs that can be repurposed to target new causes of disease, which can be cheaper than having to develop and produce new ones.

The research, led by Queen Mary and published in Molecular Cancer, is the first evidence for the genes NEK2 and INHBA causing chemoresistance in head and neck squamous cell carcinoma (HNSCC) and gene silencing of either gene overturning chemoresistance to multiple drugs.

The scientists first used a method known as data mining to identify genes that may be affecting tumor responsiveness to drug therapy. They tested 28 genes on 12 strains of chemoresistant cancer cell lines, finding four 'significant' genes that were particularly responsive that they then investigated further and tested multi-drug resistance.

Dr. Muy-Teck Teh, senior author of the study from Queen Mary University of London, said, "These results are a promising step towards cancer patients in the future receiving personalized treatment based on their genes and tumor type that give them a better survival rate and treatment outcome.

"Unfortunately, there are lots of people out there who do not respond to chemotherapy or radiation. But our study has shown that in head and neck cancers at least it is these two particular genes that could be behind this, which can then be targeted to fight against chemoresistance.

"Treatment that doesn't work is damaging both for the NHS and patients themselves. There can be costs associated with prolonged treatment and hospital stays, and it's naturally extremely difficult for people with cancer when their treatment doesn't have the results they are hoping for."

90% of all head and neck cancers are caused by HNSCCs, with tobacco and alcohol use being key associations. There are 12,422 new cases of head and neck cancer each year, and the overall five-year survival rate of patients with advanced HNSCC is less than 25%. A major cause of poor survival rates of HNSCC is because of treatment failure that stems from resistance to chemotherapy and/or radiotherapy.

Unlike lung and breast cancer patients, all HNSCC patients are treated with almost the same combinations of treatment irrespective of the genetic makeup of their cancer.

More information: Neha Khera et al, Identification of multidrug chemoresistant genes in head and neck squamous cell carcinoma cells, Molecular Cancer (2023). DOI: 10.1186/s12943-023-01846-3

https://medicalxpress.com/news/2023-09-genes-natural-toxins-cancer-patients.html

Roche seeks early-stage lung cancer use for Alecensa

 Roche plans to file its Alecensa drug for use in early-stage ALK-positive non-small cell lung cancer (NSCLC), potentially making it the first targeted therapy for these patients.

The decision comes on the back of the phase 3 ALINA study, which showed that ALK inhibitor Alecensa (alectinib) achieved a "clinically meaningful" improvement in disease-free survival (DFS) in patients with this type of cancer – a first for drugs in this therapeutic category – according to Roche.

"If approved, Alecensa has the potential to treat cancer before it has spread, in a setting where treatment can increase the chances of cure," said Levi Garraway, Roche's chief medical officer. Patients in the study had stage IB to IIIA tumours that were removed with surgery.

About half of people with NSCLC experience disease recurrence following surgery, despite adjuvant chemotherapy, and new treatments are needed to provide the best chance for cure, according to Roche. The patients in ALINA are continuing to be followed to see if the DFS improvement translates to an increase in overall survival, a secondary endpoint.

Alecensa is already approved by the FDA as a first-line therapy for patients with advanced, metastatic ALK-positive NSCLC, and Roche will now submit the ALINA data to regulators in the US, Europe, and elsewhere to try to extend its uses into the early-stage setting.

Around 5% of all NSCLC cases carry ALK mutations, and at the moment patients with advanced disease have multiple treatment options, including Alecensa, Takeda's Alunbrig (brigatinib), and Novartis' Zykadia (ceritinib), as well as Pfizer's older therapy Xalkori (crizotinib) and follow-up Lorbrena (lorlatinib).

Extending Alecensa's label to include early-stage disease would give Roche a niche free of competition from its rivals, and at the moment there is no indication that any of the other companies are testing their ALK inhibitors in early-stage patients.

ALK-positive NSCLC is often found in younger people who have a light or non-smoking history, and around half of all people with early-stage disease still experience a cancer recurrence following surgery, despite adjuvant chemotherapy.

ALINA compared Alecensa to platinum-based chemo in this post-surgery setting, but did not examine the potential benefits of using the two treatments alongside each other.

In the first half of the year, Alecensa made CHF 758 million ($$857 million) in revenues, a rise of 10%, with Roche claiming leadership in all markets for the drug in advanced ALK-positive NSCLC.

https://pharmaphorum.com/news/roche-seeks-early-stage-lung-cancer-use-alecensa

Seagen, Genmab: Improved Overall Survival in Recurrent or Metastatic Cervical Cancer

 Seagen Inc. (Nasdaq: SGEN) and Genmab A/S (Nasdaq: GMAB) announced today that the Phase 3 innovaTV 301 global trial in recurrent or metastatic cervical cancer patients with disease progression on or after front-line therapy who received TIVDAK® (tisotumab vedotin-tftv), compared with chemotherapy alone, met its primary endpoint of overall survival (OS). An Independent Data Monitoring Committee determined that OS crossed the pre-specified efficacy boundary at interim analysis. The key secondary endpoints of investigator-assessed progression-free survival and objective response rate also demonstrated statistical significance. The safety profile of TIVDAK in innovaTV 301 was consistent with the known safety profile of TIVDAK as presented in the U.S. prescribing information, and no new safety signals were observed.

The results of innovaTV 301/ENGOT cx-12/GOG 3057, a global, randomized, open-label Phase 3 trial, add to the previous results of innovaTV 204, which served as the basis for the accelerated approval of TIVDAK in the U.S. Subject to discussions with regulatory authorities, the results from innovaTV 301 are intended to serve as the pivotal confirmatory trial for the U.S. accelerated approval and support global regulatory applications. The innovaTV 301 China extension study has been initiated and continues to enroll patients, in collaboration with Zai Lab Limited.

https://finance.yahoo.com/news/seagen-genmab-announce-tivdak-tisotumab-190000237.html

Nestle-partnered weight loss capsule succeeds in pivotal trial

 A weight loss capsule developed by Nestlé (NSRGY) (NSRGF) and Epitomee Medical has succeeded in a pivotal trial

Israeli company Epitomee Medical has reported success in a pivotal study of its weight loss capsule, causing its stock to soar on the Tel Aviv Stock Exchange.

This capsule, classified as a medical device, is essentially a swallowable pill that expands in the stomach, creating a sensation of satiety. Following the announcement of this success, the company's stock surged by over 70% at one stage on Monday, reaching an all-time high and achieving a market cap of over $100 million.

It's worth noting that this stock jump occurred despite the fact that the company has not yet published the full results of the experiment; it has only reported the success. The company's report lacks crucial details, such as the average weight loss observed in the experimental group compared to the control group, and it does not specify the level of statistical significance achieved in the experiment.

The criteria for success in the experiment had been predetermined, requiring that 35% of the subjects in the trial lose more than 5% of their baseline body weight. The experiment involved 279 subjects, and Epitomee has stated that the final data will be released at a later time, once received from the external company responsible for conducting and overseeing the experiment.

Epitomee next intends to seek FDA approval for the sale of this medical device via the 510(k) pathway, which permits the sale of devices with a strong resemblance to existing devices in the market (Substantially Equivalent). This approach aims to expedite the FDA approval process by leveraging the similarities to other approved devices. The company anticipates receiving approval during 2024.

The 510(k) pathway is favored by companies looking to introduce their products to the market because it generally involves a shorter approval timeline and reduced FDA oversight compared to the full approval process. However, this route has faced criticism for its relatively lenient standards, allowing medical devices to enter the American market with greater ease.

Epitomee's weight management product is a shapeshifting polymeric scaffold composed of swellable biopolymers that imitates solid food to achieve a sensation of satiety. Once it reaches the stomach, it expands into a flexible triangle, interacting with the stomach wall and activating key pathways that regulate satiety and food intake. It is then cleared out through normal bowel movements and is not absorbed by the body. The capsule is already CE cleared.

In response to Calcalist's inquiries regarding the missing details in Epitomee's report, the Israel Securities Authority responded: "The Authority does not comment on its interactions with supervised entities, and if necessary, any such interactions will be reflected in the companies' reports."

Epitomee partnered with Nestlé Health Science in the study, with the latter having the exclusive rights to commercialize the capsule globally.

https://www.calcalistech.com/ctechnews/article/rj1g1lxah

Harm of Delaying the Disenrollment of Medicaid Ineligibles

 

Key Takeaways

1. As a result of federal and state COVID policies, there were roughly 18 million ineligible Medicaid enrollees on the program as of April 1, 2023, at an annualized cost of more than $80 billion. Paying for ineligible enrollees pulls resources away from other public priorities and primarily benefits health insurance companies that administer Medicaid.
2. States could have begun removing ineligible enrollees in April. Some states started the redetermination process early and are efficiently processing removals of ineligible enrollees, but other states are acting slowly and will waste resources on Medicaid coverage for individuals who have moved out of state, have private insurance, have died, or earn too much income.
3. Total Medicaid savings would be $41 billion and state savings would be $12 billion if all states pursued an efficient redetermination process.
4. There are significant protections for enrollees mistakenly disenrolled, including three-month retroactive eligibility, hospital presumptive eligibility, and a robust appeals process.

Three actions

States could have taken three actions to protect limited resources for eligible Medicaid recipients or for other purposes:

1. Prioritize those most likely to be ineligible: reviewing eligibility prior to the unwinding period to initiate redeterminations for those most likely to be ineligible,
2. Move up the start date: beginning redeterminations earlier, and
3. Check eligibility in bigger batches: processing a greater number of redeterminations each month.

Since about two-thirds of Medicaid is financed by the federal government, such actions would also reduce wasteful federal spending and lower the deficit.

https://paragoninstitute.org/research-paper-page-gonshorowski-blase-kleinworth-cost-of-good-intentions-medicaid-redeterminations-20230717/