Fibrolamellar Hepatocellular Carcinoma

Researchers have translated a cutting-edge tactic for treating genetic disorders into a fresh approach for potentially stymying cancer. Cell division is the generative spark of nearly every lifeform on Earth. But if healthy growth goes unchecked, cell division can turn lethal, overwhelming the organism. Such is the case with so-called oncogenes. When altered by a mutation, these growth-moderating genes go haywire, producing a geyser of cancer cells as a result. Oncogenes are also insidiously adept at generating tumors that over time become genetically "independent" from their origin, so it has been exceedingly difficult for scientists to shut down their replication at the source. Now Rockefeller University researchers have discovered a new way to target the oncogene behind a rare and often deadly liver disease using small interfering RNAs (siRNAs), an innate mechanism for silencing gene expression. As described in Molecular Therapy, the researchers slipped siRNAs inside fibrolamellar hepatocellular carcinoma (FLC) cells through a surface receptor, where they blocked the oncogene from producing illness-inducing proteins that lead to tumor formation. It's the first time that siRNAs have been used to hobble the progression of FLC, says first author Christoph Neumayer, a Ph.D. student in Rockefeller's Laboratory of Cellular Biophysics, headed by Sanford M. Simon. But the findings have wider applications as well. "That's the really exciting part," says Neumayer. "This is proof of concept that siRNAs can be used for FLC, as well as adult liver cancers, which are much more common, and other tumor types elsewhere in the body." The fusion oncogene FLC is caused by the fusion of two genes located on chromosome 19: DNAJB1, which produces heat-shock proteins that encourage cell homeostasis, and PRKACA, which produces an enzyme called kinase A that's key to cellular metabolic function. The resulting fusion, known as DNAJB1::PRKACA, brings together the proteins and a catalytic subunit of the kinase. This dysfunctional union promotes FLC formation, but how, exactly, is still unknown. Researchers in Simon's lab discovered that this fusion caused FLC in 2014, several years after Simon's own teenage daughter, Elana, was diagnosed with liver disease. After having the resulting tumor removed -- the only treatment option available to people with FLC -- Elana went on to collaborate with her father to unearth its cause, publishing the results in Science. Since then, Simon and his group have continued to reveal the mechanisms behind the disease as well as develop therapeutics. The siRNA research is part of a three-part strategy which also includes repurposing drugs for treating FLC and using molecules known as PROTACs to selectively degrade the DNAJB1::PRKACA protein that drives FLC. The drug repurposing is in advanced preparation for a clinical trial, and some of the PROTAC work is part of an international collaboration that was just awarded a $25 million Cancer Grand Challenges grant to develop treatments for high-risk, oncogene-driven cancers in children. Recently, Simon's lab discovered that they could completely stop FLC tumor growth in mice using shRNAs, short sequences of RNA that can be engineered to disrupt mRNA. The approach also caused many tumors to shrink or disappear. Having shown that quelling the fused oncogene killed tumor cells, they decided to experiment with derailing kinase A activity, which research indicated was driving tumor growth. Unlocking the cell door The problem was, fused kinase A and its "wild type" form are nearly identical, so "any drug you developed that blocks fused kinase A activity would affect all kinase A, including in normal cells," Neumayer says. "In other words, you would incur a host of problematic side effects." They had to find a way to disable toxic kinase while containing the impact so that kinase in other cells weren't affected. To do that, they specifically designed siRNAs to aim at the fusion. But because siRNAs cannot cross cell membranes, the researchers needed to figure out a way to get the siRNA inside. Luckily, a door into the cell had already been identified: a receptor called ASGR1 that's only expressed in liver cells. Its key had been too: a binding molecule known as GalNAc. Together, the duo function as a waste disposal team. GalNAc conjugate therapies, which attach siRNA molecules to the ligand to deliver therapies inside cells, are already on the market for conditions such as hereditary transthyretin-mediated amyloidosis and atherosclerotic cardiovascular disease. The team wondered if they could use the same approach to thwart the kinase driving FLC tumors. Stabilization and shrinkage To test their theory, the researchers attached a custom siRNA to the receptor's ligand and studied the method in a variety of tumor models in mice and in human cell cultures. The conjugate therapy was not only successfully delivered into the cells in all contexts, but it also caused a reduction of mRNA in the oncogene, preventing the production of the protein and resulting in the tumors stagnating or shrinking, unable to grow. They also did not detect any liver toxicity in the mice, indicating the animals tolerated the siRNAs well. "What we saw was tumor inhibition, when we had hoped to outright kill the tumor," Neumayer notes. "Our future direction will be to try to figure out how to improve that." They also tested the specificity of the siRNA by injecting it into tumor cells of another type of liver cancer. It had no toxic impact on them -- exactly as the researchers hoped. "We wanted to show that our siRNA is so targeted to the FLC fusion oncogene that it has no side effects on other cells -- even on other cancer cells," he notes. Neumayer says the findings suggest that siRNAs may be effective beyond FLC, capable of treating tumors throughout the body with a high degree of specificity: "I think siRNA medicines as a class will have a big impact over time as a new kind of genetic therapy."

Dr. Yael Mossé receives recognition for project dedicated to researching and potentially developing new therapies for undruggable solid tumors PHILADELPHIA, March 6, 2024 /PRNewswire/ -- An interdisciplinary, global team of scientists led by Yael Mossé, MD, Professor of Pediatrics in the Cancer Center at Children's Hospital of Philadelphia (CHOP), has been selected as one of five research teams from all over the world to receive funds from Cancer Grand Challenges, a funding initiative co-founded by the National Cancer Institute and Cancer Research UK. Mossé's international team will receive up to $25 million to develop transformative new therapies for previously undruggable forms of childhood cancer. Continue Reading International team led by Dr. Yael Mossé, Professor of Pediatrics in the Cancer Center at Children's Hospital of Philadelphia, will receive up to $25 million to develop transformative new therapies for previously undruggable forms of childhood cancer. Last year, 176 global teams submitted bold ideas for tackling some of the most pressing challenges in cancer research and care. Twelve teams were shortlisted, and the project "Developing a suite of oncoprotein degraders for childhood solid cancers," nicknamed Team KOODAC3, emerged as one of five teams to receive funding after a year-long rigorous selection process. The team unites the expertise of researchers from the United States, Austria, France, Germany and the United Kingdom to tackle the challenge of oncogene-addicted solid tumors in children. While survival rates for many childhood cancers have improved dramatically through the combination of standard chemotherapy and radiation therapy, survivors are often burdened with life threatening toxicities related to those therapies. Genetic discoveries related to cancer have transformed how many types of tumors are treated. Cancer is caused by genetic mutations that transform normal genes into oncogenes. These oncogenes are then translated into proteins that are not typically found in the cell, known as oncoproteins. Several drugs have been developed to treat different tumors by targeting oncogenes and their associated oncoproteins. Despite advances in this field, a critical challenge has been the difficulty of targeting proteins responsible for causing solid tumors related to childhood cancers. As a result, cure rates for most solid tumors have not improved at the rate of other types of cancer. KOODAC3 aims to develop drugs that break down or 'degrade' five of the most significant oncoproteins in children with high-risk oncogene-driven cancers, including neuroblastoma, medulloblastoma, Ewing sarcoma, fibrolamellar hepatocellular carcinoma, rhabdomyosarcoma and other cancers that deregulate these essential oncoproteins. The team is addressing this challenge by extending an ongoing collaboration with Nurix Therapeutics, a leading biopharmaceutical company focused on degrader drugs, providing a streamlined route for clinical translation of discoveries made by Team KOODAC3. Collectively, this consortium has the ambitious goal of developing oral drugs that will be deployed world-wide in partnership with a robust international patient advocacy committee that will inform outreach to childhood cancer communities globally. "Our team is deeply honored to have been selected as one of the five to receive funding from the Cancer Grand Challenges initiative," said Mossé. "Team KOODAC3 was brought together with the goal of identifying new strategies for treating high-risk pediatric cancers with a high unmet need. Each of the projects that applied for this funding were worthy, so we do not take this award lightly and we are committed to bringing our expertise together with the goal of developing paradigm-altering safe and effective new therapies for currently lethal childhood solid cancers." Additional CHOP co-investigators who are part of Team KOODAC3 include John Maris, MD, and Adam Wolpaw, MD, PhD. "At CHOP, our researchers are committed to creating life-changing solutions for children around the world, and improving the care for some of the most difficult to treat childhood cancers is what drives so much of what we do," said Susan L. Furth, MD, PhD, Executive Vice President and Chief Scientific Officer at CHOP. "We are thrilled that this prestigious organization recognized the importance of what this project is trying to achieve, and we expect the funding to help us make important strides toward our understanding of childhood cancer." The National Cancer Institute and Cancer Research UK, the world's leading funders of cancer research, co-founded and launched the Cancer Grand Challenges initiative in 2020. Cancer Grand Challenges aims to provide funding for interdisciplinary research teams from around the world whose novel ideas offer the greatest potential to advance bold cancer research and improve outcomes for people affected by cancer. The team is co-led by Martin Eilers at the University of Würzburg in Germany and is funded by Cancer Research UK, Institut National Du Cancer and KiKa (Children Cancer Free Foundation) through Cancer Grand Challenges. Learn more about the Cancer Grand Challenges at . In addition to the Team KOODAC3 award, Team MATCHMAKERS, which includes Dr. Nikolaos G. Sgourakis from CHOP, also received a Cancer Grand Challenges award of up to $25 million. About Children's Hospital of Philadelphia: A non-profit, charitable organization, Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey, as well as the Middleman Family Pavilion and its dedicated pediatric emergency department in King of Prussia. In addition, its unique family-centered care and public service programs have brought Children's Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit . Contact: Jennifer Lee Children's Hospital of Philadelphia (610)800-6592 [email protected] SOURCE Children's Hospital of Philadelphia

New Clinical Data from MD Anderson Presented at the Society for Immunotherapy of Cancer’s 38th Annual Meeting80% DCR (disease control rate) in non-radiated tumor with Durable Responses in Heavily Pretreated Patients in 6 different cancersFull data was presented at SITC’s 38th Annual Meeting; The Company will host a call at 8:30 a.m. ET today. Dial in: 877-407-0792, conference title: Clinical Significance of Plinabulin SITC Presentation with PI Dr. Steven Lin from MD Anderson NEW YORK, Nov. 07, 2023 (GLOBE NEWSWIRE) -- BeyondSpring Inc. (NASDAQ: BYSI) (“BeyondSpring” or the “Company”), a global clinical-stage biopharmaceutical company focused on using a groundbreaking technology platform for drug discovery and developing innovative therapies to improve clinical outcomes for patients with high unmet medical needs, today announced new data that translates preclinical proof-of-concept to clinical evidence of plinabulin’s immunomodulating activity. BeyondSpring and MD Anderson presented the data at the Society for Immunotherapy of Cancer's (SITC) 38th Annual Meeting on Nov 4th in San Diego, CA on an open-label, Phase 1 basket study at The University of Texas MD Anderson Cancer Center in cancer patients after progressing on PD-1, PD-L1 and/or CTLA-4 antibodies (NCT04902040) in six cancer types. Based on preclinical models, where plinabulin plus radiation and anti-PD-1 antibody enhances dendritic cell (DC) activation, T-cell proliferation, and abscopal effect, a clinical study was initiated to test these findings. At the Phase 1 data cut-off (August 31, 2023), 19 heavily pretreated patients with 6 different cancers were exposed to plinabulin (30 mg/m2) after radiation initiation to an amendable lesion (3-6 hours apart) plus anti-PD-1 antibody, including pembrolizumab or nivolumab. 11 out of 14 patients eligible for efficacy assessment per RECIST criteria and had measurable target lesion responses in the non-irradiated tumor lesion. Disease control rate evaluates the tumor reduction in non-irradiated tumor to assess abscopal effect from immune agents. 80% DCR (disease control rate) in non-irradiated tumor: In 10 immunotherapy-refractory patients of 6 different cancers (Hodgkin Lymphoma, NSCLC, SCCHN, Merkel Cell Carcinoma, RCC, Fibrolamellar HCC), plinabulin triple combination is safe and yields encouraging response with 80% disease control rate (3 PR, 5 SD, 2 PD).Durable Response in heavily pre-treated patients: 2 Hodgkin’s lymphoma patients who progressed after 12 or 16 prior lines of therapy respectively, had durable responses with one PR and one SD. These patients continued treatment after data cutoff.DC maturation in responding patients: Plinabulin administered after radiation initiation induces an early systemic immune response (detectable 3 days later) in subsets of peripheral blood DC and monocytes in patients with clinical benefits (PR+SD).Plinabulin mediates GEF-H1-dependent immune activation in responding patients: In patients with PR+SD, tumor scRNAseq analysis indicates GEF-H1-dependent immune activation in subsets of DC and monocyte-derived macrophages. Such activation was not seen in patients with PD.Additional biomarker analyses at baseline and post-treatment are underway. “There are severe unmet medical needs for cancer patients who progress on immunotherapies. We have been studying Plinabulin for 6 years, starting from preclinical proof-of-concept work in showing its DC maturation, abscopal effect and selective sequencing benefit with radiation, presented at the 2020 AACR meeting, and now the successful clinical translation in the triple IO regimen and its notable high disease control rate in these hard-to-treat and multiple refractory cancers,” Dr. Steven H. Lin, MD/PhD, professor of radiation oncology at MD Anderson commented. “These results are encouraging but preliminary. Based on the consistent mechanism in DC maturation in responding patients, this sets the stage for additional clinical studies of plinabulin/IO combinations in IO-refractory settings in a number of indications, including NSCLC and Hogkins Lymphoma.” SITC Conference Abstract Number: 732Title: Immune Activation with Plinabulin Enhances Anti-tumor response Combining Radiation with Immune Checkpoint BlockadePresenter: Steven H. Lin, MD/PhDSession: Poster Hall Phase 1 Study RegimenAll subjects received a triple combo treatment of Radiation Therapy (RT) + Plinabulin + Pembrolizumab or Nivolumab in Cycle 1, followed by the same anti-PD-1 antibody and plinabulin combo regimen in Cycle 2 and beyond until disease progression or development of unacceptable toxicity, withdrawal from study treatment, or discontinuation of this study. A short course of local consolidative RT was administered in Cycle 1 starting from Day 1. Optional sequential RT may have been administered to target other untreated lesions at discretion of the treating doctor in Cycle 2 of any regimens.Plinabulin was dosed on Day 1 and Day 4 of Cycle 1 of any anti-PD-1 regimen, and if optional RT was given in Cycle 2, Plinabulin was also given on Day 4 of Cycle 2. Plinabulin was given on Day 1 of Cycle 3 and thereafter. Anti-PD-1 antibody was dosed on Day 1 of every treatment cycle (also on Day 15 [Q4W] in case of regimen containing Nivolumab as Anti-PD-1 mAb).Subjects received the same anti-PD-1/PD-L1 mAb they failed in the prior treatment. Conference Call and Webcast InformationBeyondSpring will host a conference call and webcast today at 8:30 a.m. Eastern Time. The dial in numbers for the conference call are 1-877-407-0792 (U.S.) or 1-201-689-8263 (international). Please reference conference title: Clinical Significance of Plinabulin SITC Presentation with PI Dr. Steven Lin from MD Anderson. A live webcast will be available on BeyondSpring’s website at www.beyondspringpharma.com under “Events & Presentations” in the Investors section. An archived replay of the webcast will be available for 30 days. About BeyondSpringBeyondSpring (NASDAQ: BYSI) is a global clinical-stage biopharmaceutical company focused on developing innovative therapies to improve clinical outcomes for patients with high unmet medical needs. The Company is advancing its first-in-class lead asset, Plinabulin, as a direct anti-cancer agent in various cancer indications and to prevent chemotherapy-induced neutropenia. Its pipeline also includes three preclinical immuno-oncology assets. Additionally, BeyondSpring’s subsidiary, SEED Therapeutics, leverages a proprietary targeted protein degradation (TPD) drug discovery platform and has an initial R&D collaboration with Eli Lilly. Learn more by visiting https://beyondspringpharma.com. Investor Contact:IR@beyondspringpharma.com Media Contact:PR@beyondspringpharma.com