The Pharoah's Curse Once Killed Archaeologists. Now It Could Help Fight Cancer.
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The toxic fungus Aspergillus flavus—known as the 'Pharaoh's Curse' due to its role in the deaths of archaeologists who opened the Tomb of Tutankhamun in the 1920s—could have cancer-fighting abilities.
A new study developed ribosomally synthesized and post-translationally modified peptides (RiPPs), which produced novel structures of interlocking rings called 'asperigimycins.'
When combined with a lipid, these asperigimycins disrupted cell division in leukemia cancer cells, and were as effective as FDA-approved therapies that have treated the disease for decades.
Fungi hold a prominent place in the history of medicine. Discovered in 1928, the world's first antibiotic—penicillin–was derived from a simple mold, and since then, fungi have made their way into the ingredient lists of all kinds of immunosuppressants and cholesterol-lowering drugs. Some fungi with psychoactive properties are even being introduced in states across the U.S. as therapeutic tools.
However, not all fungi are medicinally helpful, and one of the more cursed members of the kingdom Fungi is Aspergillus flavus. A true microbial villain, this toxic fungus can produce aflatoxins, which can cause a variety of health issues and even death. The fungus garnered the cryptic nickname 'Pharaoh's Curse' due to it being linked to the deaths of several archeologists who opened ancient tombs around the world, including the famous discovery of the Tomb of Tutankhamun in the 1920s.
However, a new study published in the journal Nature Chemical Biology analyzes a wholly different aspect of this fungal villain—it's cancer-fighting properties. The group of scientists led by researchers at the University of Pennsylvania (Penn) modified A. flavus and found molecules that formed a unique structure of interlocking rings, which they named 'asperigimycins.'
When mixed with human leukemia cancer cells, these molecules—described as a class of ribosomally synthesized and post-translationally modified peptides, or RiPPs—were effective at knocking them out of commission. When the researchers added lipids (fatty molecules) to the mixture, the 'Pharaoh's Curse' transformed into a microbial blessing that worked as effectively as the FDA-approved drugs that've treated leukemia for decades.
'Fungi gave us penicillin,' Sherry Gao, senior author of the paper from Penn, said in a press statement. 'These results show that many more medicines derived from natural products remain to be found.'
To better understand the properties of these RiPPs, the scientists selectively turned genes in the leukemia cells on and off. In doing so, they found that the SLC46A3 gene was crucial for the asperigimycins to enter the cancerous cells in enough numbers to be effective. The added lipid impacts how that gene transported chemicals into the cells, increasing their potency. However, the research team confirmed that these RiPPs were only useful against leukemia cells, and appeared to have no impact on breast, liver, or lung cancer cells. So, its usefulness is specific.
Once in the cells, the asperigimycins prevent cell division, which is the process by which cancer spreads. 'Cancer cells divide uncontrollably,' Gao said in a press statement. 'These compounds block the formation of microtubules, which are essential for cell division."
The hope is to soon move testing of these compounds into animal models, and then continue onward to human trials in an effort to develop a new method of treating deadly cancers. 'Nature has given us this incredible pharmacy,' Gao said in a press statement. 'It's up to us to uncover its secrets. As engineers, we're excited to keep exploring, learning from nature and using that knowledge to design better solutions.'
What once was a pharaoh's curse might one day turn out to be an oncologist's blessing.
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At the safety update for KarMMa-3 study, one patient developed fatal neurotoxicity 43 days after ABECMA. In KarMMa, one patient had ongoing Grade 2 neurotoxicity at the time of death. Two patients had ongoing Grade 1 tremor at the time of data cutoff. Cerebral edema has been associated with ABECMA in a patient in another study in multiple myeloma. Grade 3 myelitis and Grade 3 parkinsonism have occurred after treatment with ABECMA in another study in multiple myeloma. Monitor patients at least daily for 7 days following ABECMA infusion for signs or symptoms of neurologic toxicities. Continue to monitor patients for signs or symptoms of neurologic toxicities for at least 2 weeks after ABECMA infusion and treat promptly. Rule out other causes of neurologic symptoms. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed. Counsel patients to seek immediate medical attention should signs or symptoms occur at any time. Advise patients to avoid driving for at least 2 weeks following infusion. Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS): In patients receiving ABECMA in the KarMMa and KarMMa-3 studies, HLH/MAS occurred in 2.9% (10/349) of patients. All events of HLH/MAS had onset within 10 days of receiving ABECMA, with a median onset of 6.5 days (range: 4 to 10 days) and occurred in the setting of ongoing or worsening CRS. Five patients with HLH/MAS had overlapping neurotoxicity. The manifestations of HLH/MAS include hypotension, hypoxia, multiple organ dysfunction, renal dysfunction and cytopenia. In KarMMa-3, one patient had Grade 5, two patients had Grade 4 and two patients had Grade 3 HLH/MAS. The patient with Grade 5 HLH/MAS also had Grade 5 candida sepsis and Grade 5 CRS. In another patient who died due to stroke, the Grade 4 HLH/MAS had resolved prior to death. Two cases of Grade 3 and one case of Grade 4 HLH/MAS had resolved. In KarMMa, one patient treated in the 300 x 10 6 CAR-positive T cells dose cohort developed fatal multi-organ HLH/MAS with CRS. In another patient with fatal bronchopulmonary aspergillosis, HLH/MAS was contributory to the fatal outcome. Three cases of Grade 2 HLH/MAS resolved. HLH/MAS is a potentially life-threatening condition with a high mortality rate if not recognized early and treated. Treatment of HLH/MAS should be administered per institutional guidelines. Hypersensitivity Reactions: Allergic reactions may occur with the infusion of ABECMA. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO) in ABECMA. Infections: ABECMA should not be administered to patients with active infections or inflammatory disorders. Severe, life-threatening, or fatal infections occurred in patients after ABECMA infusion. In all patients receiving ABECMA in the KarMMa and KarMMa-3 studies, infections (all grades) occurred in 61% of patients. Grade 3 or 4 infections occurred in 21% of patients. Grade 3 or 4 infections with an unspecified pathogen occurred in 12%, viral infections in 7%, bacterial infections in 4.3%, and fungal infections in 1.4% of patients. Overall, 15 patients had Grade 5 infections (4.3%); 8 patients (2.3%) with infections of pathogen unspecified, 3 patients (0.9%) with fungal infections, 3 patients (0.9%) with viral infections, and 1 patient (0.3%) with bacterial infection. Monitor patients for signs and symptoms of infection before and after ABECMA infusion and treat appropriately. Administer prophylactic, pre-emptive, and/or therapeutic antimicrobials according to standard institutional guidelines. Febrile neutropenia was observed in 38% (133/349) of patients after ABECMA infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated. Viral Reactivation: Cytomegalovirus (CMV) infection resulting in pneumonia and death has occurred following ABECMA administration. Monitor and treat for CMV reactivation in accordance with clinical guidelines. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against plasma cells. Perform screening for CMV, HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV) in accordance with clinical guidelines before collection of cells for manufacturing. Consider antiviral therapy to prevent viral reactivation per local institutional guidelines/clinical practice. Prolonged Cytopenias: In patients receiving ABECMA in the KarMMa and KarMMa-3 studies, 40% of patients (139/349) experienced prolonged Grade 3 or 4 neutropenia and 42% (145/349) experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Month 1 following ABECMA infusion. In 89% (123/139) of patients who recovered from Grade 3 or 4 neutropenia after Month 1, the median time to recovery from ABECMA infusion was 1.9 months. In 76% (110/145) of patients who recovered from Grade 3 or 4 thrombocytopenia, the median time to recovery was 1.9 months. Five patients underwent stem cell therapy for hematopoietic reconstitution due to prolonged cytopenia. The rate of Grade 3 or 4 thrombocytopenia was 62% (44/71) and 56% (135/241) for patients treated in dose range of 460 to 510 x 10 6 CAR-positive T cells and 300 to 460 x 10 6 CAR-positive T cells, respectively. Monitor blood counts prior to and after ABECMA infusion. Manage cytopenia with myeloid growth factor and blood product transfusion support according to local institutional guidelines. Hypogammaglobulinemia: In all patients receiving ABECMA in the KarMMa and KarMMa-3 studies, hypogammaglobulinemia was reported as an adverse event in 13% (46/349) of patients; laboratory IgG levels fell below 500 mg/dL after infusion in 37% (130/349) of patients treated with ABECMA. Hypogammaglobulinemia either as an adverse reaction or laboratory IgG level below 500 mg/dL after infusion occurred in 45% (158/349) of patients treated with ABECMA. Forty-one percent of patients received intravenous immunoglobulin (IVIG) post-ABECMA for serum IgG <400 mg/dL. Monitor immunoglobulin levels after treatment with ABECMA and administer IVIG for IgG <400 mg/dL. Manage appropriately per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis. Use of Live Vaccines: The safety of immunization with live viral vaccines during or after ABECMA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during ABECMA treatment, and until immune recovery following treatment with ABECMA. Secondary Malignancies: Patients treated with ABECMA may develop secondary malignancies. In KarMMa-3, myeloid neoplasms (four cases of myelodysplastic syndrome and one case of acute myeloid leukemia) occurred in 2.2% (5/222) of patients following treatment with ABECMA compared to none in the standard regimens arm at the time of the safety update. The median time to onset of myeloid neoplasm from ide-cel infusion was 338 days (Range: 277 to 794 days). Three of these five patients have died following the development of myeloid neoplasm. One out of the five cases of myeloid neoplasm occurred after initiation of subsequent antimyeloma therapy. T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including ABECMA. Mature T cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusion, and may include fatal outcomes. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Bristol Myers Squibb at 1-888-805-4555 for reporting and to obtain instructions on collection of patient samples for testing of secondary malignancy. Adverse Reactions: The most common nonlaboratory adverse reactions (incidence greater than or equal to 20%) include pyrexia, CRS, hypogammaglobulinemia, infections – pathogen unspecified, musculoskeletal pain, fatigue, febrile neutropenia, hypotension, tachycardia, diarrhea, nausea, headache, chills, upper respiratory tract infection, encephalopathy, edema, dyspnea and viral infections. Please see full Prescribing Information, including Boxed WARNINGS and Medication Guide. About Bristol Myers Squibb Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at or follow us on LinkedIn, X, YouTube, Facebook and Instagram. Cautionary Statement Regarding Forward-Looking Statements This press release contains 'forward-looking statements' within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include whether Breyanzi (lisocabtagene maraleucel) and Abecma (idecabtagene vicleucel) for the indications described in this release will be commercially successful. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb's business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2024, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise.
Time Magazine
5 hours ago
- Time Magazine
TIME100 Most Influential Companies 2025: Vertex Pharmaceuticals
Boston and London biotech company Vertex Pharmaceuticals is on a roll. In the past year and a half, Vertex worked with CRISPR Therapeutics to develop the first CRISPR treatment approved by the U.S. FDA, called Casgevy, which treats sickle-cell disease and beta thalassemia; received approval for its fifth cystic fibrosis treatment, and in January, also earned FDA approval for the first non-opioid pain killer, Journavx, in more than two decades. CEO Dr. Reshma Kewalramani is a triple threat, combining medical, research, and business experience to lead the 36-year-old company. She has continued the drug development pathway on which the company was founded: rational drug design, meaning designing drugs to address a known biological process, rather than spending time with the traditional trial and error practice of combining and testing chemicals in the hope of landing on one that has the desired effect. When faced with the myriad diseases and equally numerous targets for potential drugs the company could pursue, Kewalramani leans on a specific formula: Vertex concentrates on diseases where there aren't many treatment options, or high unmet need; they look for genetic or drug targets that animal models show can make a difference in the disease; the disease needs to have so-called biomarkers, or ways that researchers can track changes produced by the treatment; and the therapy developed should have a clear pathway for getting approval from regulatory agencies like the FDA. The approach has served the company well. Its market capitalization is around $114 billion, and total revenues were up 12% from the previous year. Treating pain in a way that avoided the addictive side effect of opioids checked all of these boxes, although it took two decades to identify the right pathway to target. 'Why did we do this? Because we thought pain was an incredibly important disease where there was no innovation and where we thought we could make a big difference,' says Kewalramani. 'And why did we keep going? Because of the science and our desire to work in areas where we could make this kind of transformative leap.' Following the launch of Casgevy, which allows people with sickle cell disease to receive a single CRISPR gene therapy to address the genetic mutation responsible for their disease, Vertex is continuing to pursue what Kewalramani calls 'one and done curative medicines.' They are in the late stages of testing a cell-based treatment for type 1 diabetes that could potentially help people skip regular insulin injections by giving them healthy insulin-making pancreatic beta cells. The company is also developing new treatments for chronic kidney disease, for which there have not been new options in almost a decade, and in 2024, Vertex bought Alpine Immune Sciences for $4.9 billion to accelerate its search for novel kidney treatments. 'We are simply not interested in making me-too medicines,' says Kewalramani.
