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P53 Antagonist Shows Early Activity in Advanced Liposarcoma

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P53 Antagonist Shows Early Activity in Advanced Liposarcoma

CHICAGO — Almost 90% of patients with metastatic liposarcoma achieved disease control with an investigational drug targeting p53 suppression, according to an early study reported at the American Society of Clinical Oncology (ASCO) annual meeting.

The results showed that 24 of 32 patients with de-differentiated liposarcoma and MDM2 amplification had stable disease and four other patients had partial responses for a disease control rate of 87.5% in response to BI 907828, an MDM2-p53 antagonist. Additionally, all 15 patients with well-differentiated liposarcoma (normally a surgically managed disease) had disease control, including four partial responses.

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In a safety cohort of 48 patients, the most common grade 3/4 treatment-related adverse events (TRAE) were neutropenia (n=10 patients), thrombocytopenia (n=9), anemia (n=5), and nausea (n=3), reported Mrinal Gounder, MD, of Memorial Sloan Kettering Cancer Center in New York City.

P53 is inactivated by missense mutations in more than half of all cancers, facilitating evasion of cell-cycle arrest and apoptosis. Overexpression of MDM2 protein is a potential inactivator of p53. Additionally, MDM2 amplification occurs across all tumor types, suggesting amplification/copy number gain is another potential mechanism by which MDM2 inactivates p53, said Gounder.

Standard of care for advanced sarcomas includes chemotherapy, tyrosine kinase inhibitors, trabectedin, and eribulin, all of which are associated with low response rates and a median overall survival of 11-20 months. In particular, systemic therapy for de-differentiated liposarcoma has limited activity, said Gounder.

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Orally available BI 907828 demonstrated antitumor activity in de-differentiated liposarcoma xenografts, providing support for a phase I trial in patients with advanced solid tumors. The first 96 patients enrolled included 49 patients with advanced liposarcoma. The dose-expansion phase continues, and enrollment has begun in a phase II/III randomized comparison against doxorubicin as initial therapy for de-differentiated liposarcoma.

Antibody-Drug Conjugate Active in mCRPC

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Almost half of patients with metastatic castration-resistant prostate cancer (mCRPC) had a PSA response when treated with an antibody-drug conjugate (ADC) targeting CD46 antigen, a phase I study showed.

Fourteen of 31 (45%) evaluable patients had at least a 50% reduction in baseline PSA level, and 10 of 21 (48%) patients evaluable for objective response had some degree of tumor regression, including four partial responses. Median duration of response exceeded 14 weeks and range of duration exceeded 31 weeks, reported Rahul Aggarwal, MD, of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center.

The ADC FOR56 consists of a fully human antibody linked with monomethyl auristatin E and targets a tumor-selective epitope of CD46, which is highly expressed in mCRPC. The epitope is accessible on tumor cells but appears to be less accessible or not fully formed on normal cells, said Aggarwal. Internalization is tumor selective.

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Preclinical studies showed that FOR56 had substantial antitumor activity, providing support for a first-in-human dose-escalation study in mCRPC with expansion cohort. Eligible patients had progressive mCRPC, prior treatment with at least one androgen signaling inhibitor, and no prior taxane treatment for mCRPC.

Study population consisted of 33 patients in the dose-escalation phase and 10 in the dose-expansion phase. Among all 43 patients, the most common (≥20%) TRAEs included neutropenia, infusion-related reaction, neuropathy, diarrhea, fatigue, nausea, decreased appetite, and alopecia. Grade 3/4 neutropenia occurred in 23 patients but no other grade 3/4 TRAEs occurred in more than two patients.

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Aggarwal said the CD46-targeting antibody might provide a platform for additional drug development, including combinations with androgen receptor-targeted treatment, bispecific T-cell engagers, and targeted radioligand therapy.

Targeting Mutant p53

A third of advanced tumors associated with the “hot spot” p53 Y220C mutation responded to a small-molecule mutation corrector, which achieved disease control in more than 60% of a small cohort.

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Among 31 patients who received the highest doses of PC14586, eight had partial responses (two unconfirmed) and 11 others had stable disease. Across all dose cohorts, 23 of 41 patients achieved disease control, reported Ecaterina E. Dumbrava, MD, of the MD Anderson Cancer Center in Houston. Reduction in target lesion size occurred in multiple tumor types, including partial responses in prostate, ovarian, breast, endometrial, pancreatic, and small-cell lung cancer.

TRAEs were generally grade 1/2. At the highest dose levels, the most common grade 3 TRAEs were increased ALT and anemia; one patient had grade 4 immune thrombocytopenia.

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TP53 mutations are the most common genomic events in human cancer, including 10 so-called “hot spot” mutations that account for about 30% of all TP53 mutations. The p53 Y220C hot-spot mutation occurs in about 1% of all solid tumors and has a destabilizing effect on p53 protein. PC14586 stabilizes p53 Y220C mutant protein to restore p53 transcription and tumor-suppressor function, said Dumbrava.

Enrollment in the trial will continue at dose levels lower than the maximum tolerated dose to help determine the recommended phase II dosing.

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007. Follow

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Disclosures

The study of BI 907828 was supported by Boehringer Ingelheim.

Gounder disclosed relationships with Flatiron Health, Guidepoint Global, Med Learning Group, Medscape, More Health, PER, touchIME, Ayala Pharmaceuticals, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Epizyme, Karyopharm Therapeutics, SpringWorks Therapeutics, Tyme, Amgen, and UpToDate, as well as patent/royalty/intellectual property interests.

The study of FOR46 was supported by Fortis Therapeutics.

Aggarwal disclosed relationships with Clovis Oncology, Advanced Accelerator Applications, Alessa Therapeutics, Amgen, AstraZeneca, Axiom Biotechnologies, Dendreon, Jubilant Pharmaceuticals, Merck, Pfizer, AbbVie, BioXCel Therapeutics, Cancer Targeted Technology, Janssen, Novartis, Xynomic Pharma, and Zenith Epigenetics.

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The study of PC14586 was supported by PMV Pharmaceuticals.

Dumbrava disclosed relationships with Aileron Therapeutics, Amgen, Aprea Therapeutics, Astex Pharmaceuticals, Bayer, Bellicum Pharmaceuticals, Bolt Biotherapeutics, Compugen, Gateway Foundation, Immunocore, Immunomedics/Gilead Sciences, Mereo BioPharma 5, PMV Pharma, Rain Therapeutics, Sanofi, Seattle Genetics, TRACON Pharma, Triumvira Immunologics, and Unum Therapeutics.

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Lululemon Is Moving Tons of Summer-Ready Apparel to Sale Right Now

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Lululemon Is Moving Tons of Summer-Ready Apparel to Sale Right Now

lululemon sale june 2022

Courtesy of Retailer

When it comes to curating a sale that us guys actually want to shop, Lululemon is one of the best at making it happen. Recently, the legacy performance wear brand added tons of summer-ready apparel to its We Made Too Much sale section. While supplies last, you can shop up to 50% off some of Lululemon’s best-selling styles in shorts, tees, swimwear, and more.

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While there’s a ton of gym wear in this sale, our favorite aspect is the surprising amount of casual pieces you can find. Because Lululemon has some of the best lightweight and breathable fabric blends around, you can pick up sleek garments like the Venture Long Sleeve Shirt (50% off) and ABC Jogger (30% off) and wear them out to your summer dinners without feeling too dressed-down. And if you’re looking for casual clothes with versatility—like pieces you can wear to play golf or to a ball game—you can find several colors on sale in styles like the Airing Easy Short Sleeve Buttondown (27% off) and the City Sweat Short (43% off).

The best deals are the ones you get to first, so make sure to act fast on these new sale styles. Whether you’re looking for new gym gear or everyday apparel, we’ve got you covered on all the latest sale restocks from Lululemon!

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Venture Long Sleeve Shirt

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Gear and Commerce Editor
John Thompson is the Gear and Commerce Editor at Men’s Health, where he covers fashion, grooming, gear, and technology.

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Everything We Know About Umbrella Academy Season 4

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Everything We Know About Umbrella Academy Season 4

Warning: This article contains spoilers for Umbrella Academy Season 3.


The Umbrella Academy family has been through a lot. They’ve traveled through time, stopped the apocalypse twice, and done it all in a matter of days, if we’re tracking their achievements in real time. Still, the team’s unexpected superhero days are far from over.

At the end of Season 3, we didn’t get many answers, just more questions. Now that our world is destroyed, where did everyone end up? How are Allison’s daughter and Ray together in the same timeline? Where’s Sloane? And what is the Sparrow Academy’s Ben doing on that train? Is there any way to return the world to how it was?

That’s not even mentioning Reginald Hargreeves. Despite how he came off to Klaus throughout most of Season 3, Reginald is still as devious as ever. But from the Season 3 finale, it looks like we’ll finally get some clarity on what all his secret planning was for. It looks like he has a woman named Abigail standing with him in the new reality he destroyed the world to create. And if his willingness to trick his children and the Umbrella Academy into doing his bidding is any indication, he’ll do anything to get what he wants. The remaining Sparrows and the Umbrella Academy may all have to band together to defeat Reginald.

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The only thing we know for sure is that there’s a clear set-up for a Season 4 of The Umbrella Academy. Here’s everything we know about a potential Season 4 of The Umbrella Academy. We’ll update this space with the latest news.

Will There Be a Season 4 of The Umbrella Academy?

Since the show’s Season 3 just premiered, it could be too soon for Netflix to give it a green light. How many people tune into the new season could be the data the streaming service uses to determine whether or not The Umbrella Academy gets a renewal.

Steve Blackman, who created the Netflix adaptation of The Umbrella Academy, told Men’s Health he already has plans for what he wants to do for the next season, and will answer many of the unanswered questions left after the Season 3 finale, including that mysterious post-credits scene.

“I can only tell you it is the Ben from the Sparrow timeline,” Blackman says. “It is the Ben you’ve seen all season long. I can’t tell you why he’s there, or what the glasses are all about, but that is the Ben from the Sparrow Academy. Everything else will be answered next year.”

He also revealed to The Wrap that he initially pitched the show to last for four seasons, but there’s been no word yet on if it’ll actually be the end for the superpowered family.

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“I think if we got to Season 4, it would be a great ending for the run of the show,” he told the publication. “I’m not saying I couldn’t do more, but you know, I think that would be very satisfying for the audience, four seasons.”

Having said all that, Netflix only has one more season of Stranger Things, and after that, The Umbrella Academy may just be its most popular genre show. It would be shocking if we didn’t see the Umbrellas (and the remaining Sparrows) back for more.

When Will Season 4 of The Umbrella Academy come out?

Until we get official confirmation of another season, we can’t say anything for sure. But in the meantime, get clarity on some of the major twists in Season 3, like who the mysterious old man is, or a breakdown of the Sparrow Academy, and check out our interview with creator Steve Blackman.

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Fit Kids More Likely to Stay Mentally Sharp with Age: Study

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Fit Kids More Likely to Stay Mentally Sharp with Age: Study

June 27, 2022 – Physical activity helps kids build strong muscles and bones and lowers the risk of things like heart disease and diabetes later in life. Now, there’s yet another reason to encourage your child to move: It may help them stay mentally sharp for decades.

A new study done by researchers in Australia followed 1,200 people for 30 years and revealed a link between childhood fitness and mental performance in middle age.

The study began in 1985. It looked at people between the ages of 7 and 15 at the time, who were assessed for heart and lung fitness, power, and endurance, and measured for waist-to-hip ratio. More than 30 years later, those with the highest fitness scores and lower waist-to-hip ratios as kids tended to score better in tests of their thinking skills.

The results, published in the Journal of Science and Medicine in Sport, underline the importance of exercise not just for a healthy body but for a healthy brain. And to reap the full benefit, we may need to start as far back as early childhood.

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Fit Body, Fit Brain

Previous research has linked adult fitness with better thinking skills and a lower risk of dementia later in life, though this study is the first to link childhood fitness to those outcomes.

That link remained even after controlling for things like academic performance, social and economic status, smoking, and alcohol consumption, says Michele Callisaya, PhD, a study co-author and associate professor from the National Centre for Healthy Ageing at Peninsula Health and Monash University in Melbourne, Australia. (Researchers from the University of Tasmania also worked on the study.)

High fitness levels help new neurons, connections, and blood vessels form in the brain, Callisaya says, which may explain the protective effect. What’s more, healthy behaviors may be more likely to stick if we start when we’re young, she says.

One surprising finding: While being fit as a kid was linked to higher scores in things like processing speed and attention, it had no impact on memory.

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“This might be because the cognitive functions of processing speed and attention start to decline in midlife,” Callisaya says. “Memory generally starts to decline later.”

Tips for Parents

Children over 6 should get at least 60 minutes of moderate to vigorous activity every day, according to the U.S. physical activity guidelines. That’s in line with Australian guidelines as well, Callisaya notes.

“It’s important to remember this can be doing fun things like running around the park,” she says. “Making physical activity a positive experience and fun is important.”

And be sure you get in there and run around with them: Setting a good example is a key way to help prevent health problems, she says.

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And here’s another strategy: Try cutting back on screen time. A separate study from Denmark suggests this may be a good way to get kids moving more. In fact, kids whose screen time was limited to 3 hours a week had an average of 45 minutes more daily physical activity than those not given a limit.

Surprisingly, screen limits had no impact on the physical activity of parents who also took part in the study, the researchers noted – maybe because children are more spontaneous in their physical activity, compared to adults.

In other words, persuading children to be more active could simply mean encouraging kids to be just that: kids.

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