SLFN11

Chemotherapy kills cancer cells. But the way these cells die appears to be different than previously understood. Researchers have now uncovered a completely new way in which cancer cells die: due to the Schlafen11 gene. 'This is a very unexpected finding. Cancer patients have been treated with chemotherapy for almost a century, but this route to cell death has never been observed before. Where and when this occurs in patients will need to be further investigated. This discovery could ultimately have implications for the treatment of cancer patients.' Chemotherapy kills cancer cells. But the way these cells die appears to be different than previously understood. Researchers from the Netherlands Cancer Institute, led by Thijn Brummelkamp, have uncovered a completely new way in which cancer cells die: due to the Schlafen11 gene. "This is a very unexpected finding. Cancer patients have been treated with chemotherapy for almost a century, but this route to cell death has never been observed before. Where and when this occurs in patients will need to be further investigated. This discovery could ultimately have implications for the treatment of cancer patients." They publish their findings in Science. Many cancer treatments damage cell DNA. After too much irreparable damage, cells can initiate their own death. High school biology teaches us that the protein p53 takes charge of this process. p53 ensures repair of damaged DNA, but initiates cell suicide when the damage becomes too severe. This prevents uncontrolled cell division and cancer formation. Surprise: unanswered question That sounds like a foolproof system, but reality is more complex. "In more than half of tumors, p53 no longer functions," says Thijn Brummelkamp. "The key player p53 plays no role there. So why do cancer cells without p53 still die when you damage their DNA with chemotherapy or radiation? To my surprise, that turned out to be an unanswered question." His research group then discovered, together with the group of colleague Reuven Agami, a previously unknown way in which cells die after DNA damage. In the lab, they administered chemotherapy to cells in which they carefully modified the DNA. Thijn: "We were looking for a genetic change that would allow cells to survive chemotherapy. Our group has a lot of experience in selectively disabling genes, which we could perfectly apply here."* New key player in cell death By switching off genes, the research group found a new pathway to cell death headed by the gene Schlafen11 (SLFN11). Principle investigator Nicolaas Boon: "In the event of DNA damage, SLFN11 shuts down the protein factories of cells: the ribosomes. This causes immense stress in these cells, which leads to their death. The new route we discovered completely bypasses p53." The SLFN11 gene is not unfamiliar in cancer research. It is often inactive in tumors of patients who do not respond to chemotherapy, says Thijn. "We can now explain this link. When cells lack SLFN11 they will not die in this manner in response to DNA damage. The cells will survive and the cancer persist." Impact on cancer treatment "This discovery uncovers many new research questions, which is usually the case in fundamental research," says Thijn. "We have demonstrated our discovery in lab-grown cancer cells, but many important questions remain: Where and when does this pathway occur in patients? How does it affect immunotherapy or chemotherapy? Does it affect the side effects of cancer therapy? If this form of cell death also proves to play a significant role in patients, this finding will have implications for cancer treatments. These are important questions to investigate further." *Turning off genes, one by one People have thousands of genes, many of which have functions that are unclear to us. To determine the roles of our genes, researcher Thijn Brummelkamp developed a method using haploid cells. These cells contain only one copy of each gene, unlike the regular cells in our bodies that contain two copies. Handling two copies can be challenging in genetic experiments, because changes (mutations) often occur in just one of them. This makes it difficult to observe the effects of these mutations. Together with other researchers, Brummelkamp has been unraveling processes that are crucial in disease for years using this versatile method. For example, his group recently discovered that cells can make lipids in a different way than previously known. They uncovered how certain viruses, including the deadly Ebola virus, manage to enter human cells. They delved into cancer cell resistance against specific therapies and identified proteins that act as brakes on the immune system, which is relevant to cancer immunotherapy. Over the last years, his team discovered two enzymes that had remained elusive for four decades, and that turned out to be vital for muscle function and brain development. This research was financially supported by KWF Dutch Cancer Society, Oncode Institute, and Health Holland.

SAN FRANCISCO, Feb. 05, 2024 (GLOBE NEWSWIRE) -- ProLynx Inc. announced today that the first patient was treated with PLX038 (PEGylated SN-38) in a Phase I/II clinical trial for primary CNS tumors driven by MYC or MYCN amplifications. National Institutes of Health’s NCI investigators Dr. Marta Penas-Prado and Dr. Mark Gilbert are conducting the trial. MYC genes regulate expression of genes involved in cell division. High levels of MYC drive oncogenesis in many cancers and induce DNA changes leading to the formation of “topoisome complexes”. MYC and MYCN amplifications are seen in multiple primary tumors of the central nervous system (CNS). This includes 30% of relapsed medulloblastomas, and MYCN-amplified ependymoma, characterized by aggressive clinical behavior and treatment resistance. The MYC or MYCN-induced topoisome contains high levels of topoisomerases that should be susceptible to topoisomerase inhibitors. PLX038 is a long-acting prodrug of the topoisomerase 1 inhibitor, SN-38 – the active metabolite of irinotecan and sacituzumab govitecan. PLX038 is unique as the SN-38 is covalently bound to a circulating nanomolecule and is slowly released to provide free SN-38 with a long half-life, low Cmax and very high exposure – important for optimal safety and efficacy. Importantly, in preclinical studies, PLX038 was shown to accumulate in CNS tumors, where it slowly releases SN-38. The NCI trial will assess whether PLX038 is safe and efficacious in primary CNS tumors driven by MYC or MYCN amplifications. The Phase I trial will confirm the recommended Phase II dose. The Phase II trial will test PLX038 in 3 independent cohorts: 1) newly diagnosed MYCN-amplified ependymoma, 2) recurrent ependymoma or medulloblastoma with MYCN or MYC amplification, and 3) other recurrent primary CNS tumors with MYC or MYCN amplifications. Notably, the Phase II trial will incorporate on-treatment tumor biopsies to investigate biomarkers of response and resistance, including SLFN11, MYC, MYCN and Top1, 2a, and 2b expression. This data could prospectively identify patients most responsive to the drug. Additionally, working collaboratively with The Office of Patient-Centered Outcomes (OPCORe), researchers will collect patient-reported outcomes (PROs) to measure the impact of therapy, including toxicity, symptom severity and interference with daily activities, and physical functioning. ProLynx co-founder, Daniel V. Santi, stated, “We are excited to work with NCI investigators to bring novel treatments to patients with rare CNS cancers, in hope of improving their outcomes.” He added, “Conventional short-acting topoisomerase 1 inhibitors have clinical activity in certain CNS tumors. Accordingly, we are optimistic that a long-acting SN-38 will result in increased efficacy and safety.” Additional information on this clinical trial is available at clinicaltrials.gov, through identifier number NCT06161519. For patients interested in enrolling in this clinical trial, please call NCI’s toll-free number: 1-800-4-Cancer (1-800-422-6237) (TTY: 1-800-332-8615); visit the website: and/or email: NCIMO_referrals@mail.nih.gov. ProLynx is a San Francisco biotechnology company developing proprietary systems to improve the pharmacokinetics/efficacy of important drugs ( ).

DUBLIN, March 15, 2023 /PRNewswire/ -- Jazz Pharmaceuticals, Inc. (Nasdaq: JAZZ) today announced that the company, along with its partners, will present five new abstracts at the American Association for Cancer Research (AACR) Annual Meeting from April 14-19, 2023. Research findings to be presented include data from company-sponsored and collaborative trials studying Zepzelca® (lurbinectedin), zanidatamab and JZP898. "The data Jazz and our partners are presenting at AACR this year demonstrate our commitment to advancing the next generation of oncology care, including our ongoing research for lurbinectedin," said Rob Iannone, M.D., M.S.C.E., executive vice president, global head of research and development of Jazz Pharmaceuticals. "Over the last year, Jazz has added promising new immuno-oncology and targeted therapy candidates to our pipeline – including zanidatamab, a novel late-stage HER2-targeted bispecific antibody – and progressed ongoing development programs with the goal of improving standards of care across multiple cancer types with significant unmet need and poor outcomes." Data highlights at the AACR Annual Meeting include: A poster presentation evaluating the role of SLFN11 expression in predicting response to lurbinectedin, a DNA damaging agent, in human small cell lung cancer (SCLC) cell lines and in vivo models. Results demonstrate that efficacy may be correlated to SLFN11 protein expression, consistent with the RNA level association.1 A poster presentation featuring data identifying MCL1 as a specific lurbinectedin target and demonstrating anti-tumor activity of lurbinectedin in combination with a specific BCL2 inhibitor and with a specific BCL2L1 inhibitor in in vivo and in vitro models.2 A poster presentation titled "ERBB2 amplification detected in ctDNA as a surrogate for tumor tissue FISH analysis of HER2 status in phase 1 study with zanidatamab for the treatment of locally advanced or metastatic HER2 expressing cancers." The AACR abstracts are available at: The full list of Jazz-supported presentations at the 2023 AACR Annual Meeting are: Zepzelca® (lurbinectedin) Presentations Zanidatamab Presentation* JZP898 Presentation About Zanidatamab Zanidatamab is an investigational bispecific antibody, based on Zymeworks' Azymetric™ platform, that can simultaneously bind two non-overlapping epitopes of HER2, known as biparatopic binding. This unique design results in multiple mechanisms of action including dual HER2 signal blockade, increased binding and removal of HER2 protein from the cell surface, and potent effector function leading to encouraging antitumor activity in patients. Zymeworks, along with collaborators Jazz and BeiGene, Ltd. (BeiGene), are developing zanidatamab in multiple clinical trials as a targeted treatment option for patients with solid tumors that express HER2. The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for zanidatamab in patients with previously treated HER2 gene-amplified biliary tract cancers (BTC), and two Fast Track designations for zanidatamab: one as a single agent for refractory BTC and one in combination with standard of care chemotherapy for first-line GEA. Additionally, zanidatamab has received Orphan Drug designations from FDA for the treatment of BTC and GEA, as well as Orphan Drug designation from the European Medicines Agency for the treatment of gastric cancer. Zanidatamab was also granted Breakthrough Therapy designation from the Center for Drug Evaluation (CDE) in China. About Zepzelca® (lurbinectedin) Zepzelca is an alkylating drug that binds guanine residues within DNA. This triggers a cascade of events that can affect the activity of DNA binding proteins, including some transcription factors, and DNA repair pathways, resulting in disruption of the cell cycle and eventual cell death.3 The FDA approved Zepzelca under accelerated approval in June 2020 for the treatment of adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy. The approval is based on overall response rate (ORR) and duration of response demonstrated in an open-label, monotherapy clinical study. In December 2021, Jazz and PharmaMar announced the initiation of LAGOON, a confirmatory Phase 3 clinical trial of Zepzelca for the treatment of patients with relapsed small cell lung cancer. If successful, LAGOON will serve as the confirmatory trial for Zepzelca to support full approval in the U.S. Zepzelca is a prescription medicine used to treat adults with small cell lung cancer that has spread to other parts of the body (metastatic) and who have received treatment with chemotherapy that contains platinum, and it did not work or is no longer working. Zepzelca is approved based on response rate and how long the response lasted. Additional studies will further evaluate the benefit of Zepzelca for this use. Zepzelca is not approved as part of a combination therapy or as a first-line maintenance treatment for patients with extensive-stage small cell lung cancer. Important Safety Information for Patients Before receiving ZEPZELCA, tell your healthcare provider about all of your medical conditions, including if you: have liver or kidney problems. are pregnant or plan to become pregnant. ZEPZELCA can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider should do a pregnancy test before you start treatment with ZEPZELCA. You should use effective birth control (contraception) during treatment with and for 6 months after your final dose of ZEPZELCA. Tell your healthcare provider right away if you become pregnant or think that you are pregnant during treatment with ZEPZELCA. Males with female partners who are able to become pregnant should use effective birth control during treatment with and for 4 months after your final dose of ZEPZELCA. Females who are breastfeeding or plan to breastfeed. It is not known if ZEPZELCA passes into your breastmilk. Do not breastfeed during treatment with ZEPZELCA and for 2 weeks after your final dose of ZEPZELCA. Talk to your healthcare provider about the best way to feed your baby during treatment with ZEPZELCA. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Certain other medicines may affect how ZEPZELCA works. What should I avoid while using ZEPZELCA? Avoid eating or drinking grapefruit, or products that contain grapefruit juice during treatment with ZEPZELCA. ZEPZELCA can cause serious side effects, including: Low blood cell counts. Low blood counts including low neutrophil counts (neutropenia) and low platelet counts (thrombocytopenia) are common with ZEPZELCA, and can also be severe. Some people with low white blood cell counts may get fever, or an infection throughout the body (sepsis), that can cause death. Your healthcare provider should do blood tests before you receive each treatment with ZEPZELCA to check your blood cell counts. Tell your healthcare provider right away if you develop: fever or any other signs of infection unusual bruising or bleeding tiredness pale colored skin Liver problems. Increased liver function tests are common with ZEPZELCA, and can also be severe. Your healthcare provider should do blood tests to check your liver function before you start and during treatment with ZEPZELCA. Tell your healthcare provider right away if you develop symptoms of liver problems including: loss of appetite nausea or vomiting pain on the right side of your stomach area (abdomen) Your healthcare provider may temporarily stop treatment, lower your dose, or permanently stop ZEPZELCA if you develop low blood cell counts or liver problems during treatment with ZEPZELCA. The most common side effects of ZEPZELCA include: Tiredness low white and red blood cell counts increased kidney function blood test (creatinine) increased liver function blood tests increased blood sugar (glucose) nausea decreased appetite muscle and joint (musculoskeletal) pain low level of albumin in the blood constipation trouble breathing low levels of sodium and magnesium in the blood vomiting cough diarrhea These are not all of the possible side effects of ZEPZELCA. Call your doctor for medical advice about side effects. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit or call 1-800-FDA-1088. You may also report side effects to Jazz Pharmaceuticals at 1-800-520-5568. More information about Zepzelca, including Full Prescribing Information and Patient Information, is available here. ZEPZELCA is a trademark of Pharma Mar, S.A. used by Jazz Pharmaceuticals under license. About JZP898 JZP898 (also known as WTX-613) is an investigational differentiated, conditionally-activated interferon alpha (IFNα) INDUKINE™ molecule. JZP898 is an engineered IFN⍺2b cytokine pro-drug that is activated specifically within the tumor microenvironment where it can stimulate IFNα receptors on cancer-fighting immune effector cells. JZP898 was created leveraging Werewolf Therapeutics' proprietary PREDATOR™ protein engineering technology, which integrates specialized protein design elements to enhance activity, stability and tumor selectivity within a single molecule, called INDUKINE molecules. About Jazz Pharmaceuticals plc Jazz Pharmaceuticals plc (Nasdaq: JAZZ) is a global biopharmaceutical company whose purpose is to innovate to transform the lives of patients and their families. We are dedicated to developing life-changing medicines for people with serious diseases—often with limited or no therapeutic options. We have a diverse portfolio of marketed medicines and novel product candidates, from early- to late-stage development, in neuroscience and oncology. Within these therapeutic areas, we are identifying new options for patients by actively exploring small molecules and biologics, and through innovative delivery technologies and cannabinoid science. Jazz is headquartered in Dublin, Ireland and has employees around the globe, serving patients in nearly 75 countries. Please visit for more information. Caution Concerning Forward-Looking Statements This press release contains forward-looking statements, including, but not limited to, statements related to paving the way for next-generation precision therapies for patients and improving the standard of care for these serious and life-threatening cancers and other statements that are not historical facts. These forward-looking statements are based on Jazz Pharmaceuticals' current plans, objectives, estimates, expectations and intentions and inherently involve significant risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, without limitation, risks and uncertainties associated with pharmaceutical product development, and other risks and uncertainties affecting Jazz Pharmaceuticals and its development programs, including those described from time to time under the caption "Risk Factors" and elsewhere in Jazz Pharmaceuticals plc's Securities and Exchange Commission filings and reports (Commission File No. 001-33500), including Jazz Pharmaceuticals' Annual Report on Form 10-K for the year ended December 31, 2022 and future filings and reports by Jazz Pharmaceuticals. Other risks and uncertainties of which Jazz Pharmaceuticals is not currently aware may also affect Jazz Pharmaceuticals' forward-looking statements and may cause actual results and the timing of events to differ materially from those anticipated. The forward-looking statements herein are made only as of the date hereof or as of the dates indicated in the forward-looking statements, even if they are subsequently made available by Jazz Pharmaceuticals on its website or otherwise. Jazz Pharmaceuticals undertakes no obligation to update or supplement any forward-looking statements to reflect actual results, new information, future events, changes in its expectations or other circumstances that exist after the date as of which the forward-looking statements were made. Contacts: Jazz Media Contact: Kristin Bhavnani Head of Global Corporate Communications Jazz Pharmaceuticals plc CorporateAffairsMediaInfo@jazzpharma.com Ireland +353 1 637 2141 U.S. +1 215 867 4948 Jazz Investor Contact: Andrea N. Flynn, Ph.D. Vice President, Head, Investor Relations Jazz Pharmaceuticals plc investorinfo@jazzpharma.com Ireland +353 1 634 3211 U.S. +1 650 496 2717 References: 1 2 3 ZEPZELCA (lurbinectedin) Prescribing Information. Palo Alto, CA: Jazz Pharmaceuticals, Inc. Company Codes: NASDAQ-NMS:JAZZ