Small molecules Archives

Around 400,000 children are diagnosed with cancer every year, according to the World Health Organization (WHO). But since the 1970s, the cancer death rate has declined by more than half in children and adolescents, largely due to improvements in pediatric cancer care. As we observe International Childhood Cancer Day today, let us take a look at some of the recent advancements in childhood cancer research. CAR-T therapies on the horizon for childhood cancers Chimeric antigen receptors (CAR)-T therapy has widened treatment options for adults with blood cancers. However, barely any CAR-T therapies for children have made it to the market. In fact, to date, only Swiss pharmaceutical Novartis’ Kymriah has been approved by the U.S. Food and Drug Administration (FDA) for children and young adults with refractory or relapsed B cell acute lymphoblastic leukemia, a type of blood cancer in which the bone marrow produces too many abnormal white blood cells called B lymphocytes. How CAR-T therapy works is by reprogramming a patient’s own T cells with a CAR to recognize and target specific proteins or cancer cells. Kymriah binds to CD19, a protein that is expressed in B cell blood cancers like B cell acute lymphoblastic leukemia, and attacks and kills cancer cells. But like most CAR-T therapies, Kymriah is associated with a risk of cytokine release syndrome (CRS) and other neurotoxicities that are caused by the rapid immune activation in the body, which can be life-threatening. While Kymriah is the only available CAR-T drug for pediatric cancers in the U.S., efforts are being made to get regulators to open their arms to more CAR-T drugs. U.S.-based BrainChild Bio, a spin-out of Seattle Children’s Hospital, is solely focused on treating childhood cancers. It aims to treat brain tumors in children, like diffuse intrinsic pontine glioma (DIPG), which is an aggressive kind of childhood cancer that forms in the brainstem. DIPG is the most common form of brain tumor in children, and accounts for 80% of cases. Last year, BrainChild took its CAR-T candidate to the clinic to evaluate four different targets. It plans to create a CAR-T cell therapy platform that can address multiple targets, include new transgenes that offer a more targeted approach, and minimize the risk of neurotoxicities. “Developing therapies that are tailored specifically for pediatric patients will generate better medicines to address CNS tumors while protecting these young patients and their developing bodies and minds,” said Nicholas Vitanza, CNS CAR-T cell lead and DIPG research lead at Seattle Children’s, and the founding chair of Brainchild Bio’s Scientific Advisory Board, in a press release. As we cannot count on trickle-down therapeutic approaches - which rely on the assumption that a drug that works for adults will work for kids as well - because pediatric cancers are unique, BrainChild’s pediatric cancer-targeted therapeutic approach could push for an FDA nod quicker. Clinical anti-GD2 antibody poised for FDA win? As the immunotherapy landscape continues to evolve, U.K.-based Renaissance Pharma looks to take on a rare tumor called neuroblastoma. Around 90% of all neuroblastoma patients are under the age of five. It occurs when nerve tissues that aren’t fully developed grow out of control, often due to a genetic mutation. The continuous proliferation of these cells results in the formation of a tumor. As neuroblastomas predominantly express the molecule GD2, Renaissance’s lead candidate Hu14.18 is a humanized, anti-GD2 antibody. When an anti-GD2 antibody is combined with chemotherapy in newly diagnosed patients, this enhances the anti-tumor effect. Renaissance’s Hu14.18 in combination with chemotherapy, was found to have an overall survival rate of 86%, and all patients in the trial exhibited clinical benefit. Other anti-GD2 antibodies include U.S.-based United Therapeutics’ Unituxin and British biotech company EUSA Pharma’s Qarziba, both of which are in the market after securing FDA stamps, but unlike Hu14.18, they are chimeric antibodies. As Hu14.18 is 98% human, it carries a lower risk for immunogenicity, which is the ability of a foreign substance to provoke an immune response. The only humanized anti-GD2 antibody that is sold is naxitamab under the brand name Danyelza, and developed by Y-mAbs Therapeutics. But since Danyelza is only prescribed to patients with relapsed or refractory forms of the disease, if approved, Renaissance’s drug combination could fill the treatment gap in early-stage neuroblastoma. And it seems to be getting closer as the candidate had encouraging phase 2 results. In the study, 64 patients were given chemotherapy drugs along with Hu14.18, after which, they received radiation therapy and further immunotherapy. In 42 of the patients, a 75% reduction in tumor was observed after two chemotherapy-immunotherapy cycles. Then, at the end of three years post-treatment, a 73.7% event-free survival and overall survival of 86% were achieved. Childhood cancer research: small molecule drugs in the making Meanwhile, small molecules like tyrosine kinase inhibitors are gaining recognition in the childhood cancer space, according to Alex Huang, co-leader of Immune Oncology Scientific Program, Case Comprehensive Cancer Center at Case Western Reserve University. As the name suggests, tyrosine kinase inhibitors block the enzyme tyrosine kinase. This enzyme sends growth signals to cells, so halting its production can control cancer cell growth. Recently, the FDA cleared bosutinib to treat certain children aged one year and older with chronic myeloid leukemia (CML), which is caused by the abnormal Philadelphia chromosome. Previously authorized for adults with CML, researchers at the Leukemia & Lymphoma Society in the U.S., saw encouraging results in children. Around 75% of the children who participated in the trial responded to the treatment, and had a reduction in the number of cancer cells in the bone marrow. The drug targets tyrosine kinase as well as another enzyme called SRC to limit cancer cell growth. However, it does come with a warning that children may experience side effects like abdominal pain, rash, fatigue, and vomiting. Over the past few years, other tyrosine kinase inhibitors like dasatinib and nilotinib were greenlit by the FDA, and are currently regarded as first-line chemotherapy agents in pediatric CML. However, the use of these drugs is different in children and adults. In children, treatment takes longer and so, adverse effects could be more common among this cohort. There is also a dearth of research in young patients partly because CML is rare in children, and fewer clinical trials take place. Apart from tyrosine kinase inhibitors, Oncoheroes Biosciences’ volasertib is another small molecule that is being developed to treat rhabdomyosarcoma, a rare pediatric soft tissue cancer. As polo-like kinase 1 (PLK-1) is a known cancer target, this PLK-1 inhibitor obtained Rare Pediatric Disease Designation and Orphan Drug Designation from the FDA nearly four years ago, and is presently in the clinic. Childhood cancer funding among challenges to battle Although different kinds of treatment are being tested in the clinic, Huang believes that there is room for more progress. He pointed out that there is a need for “novel cancer models that can accurately mimic rare cancer behavior, and utilization of drug screening for better prediction of response and for individualized treatment options.” To add to that, he thinks that fewer doctors want to specialize in pediatric cancer, at present. “Another pressing issue is the alarming drop in physicians and physician-scientists who are expressing an interest in pursuing a career as a pediatric cancer doctor or research as evidenced by the recent drop in Pediatric Hematology-Oncology Clinical Fellowship program. This is a worrisome trend which directly affects the pipeline of future leaders and thinkers in the field,” said Huang. Moreover, the childhood cancer field could do with more money being spent on research and development. In the U.K., pediatric cancers have gotten the short end of the stick, as only 2% of cancer research funding is dedicated to fighting children's cancer, according to a report. And, in the U.S., it’s not much better. Childhood cancer research comprises roughly 4-5% of National Cancer Institute (NCI) funding, Huang pointed out. Why is childhood cancer research underfunded? “As a rare disease group, it is challenging to incentivize industry to invest in new drug development solely for pediatric cancer. And since the disease is rare, it is challenging to collect sufficient specimens to be widely shared for research purposes, or to do multiple clinical trials with sufficient patient enrollment without a consortium, making large institutional-based clinical trials difficult to implement,” said Huang. “Historically, pediatric cancer researchers have relied heavily on philanthropy and foundation support, due to high enthusiasm among families and supporters affected or motivated by childhood cancer.” Now, Huang believes that it is up to the federal agencies like the National Institutes of Health (NIH) and the FDA “to incentivize the private sector, and academia to partner with a focus on solving rare disease.” Nevertheless, public awareness is growing and grassroots organizations continue to focus on hard-to-treat childhood cancers like refractory sarcoma and DIPT, according to Huang. And with more money invested in childhood cancer research, more drugs can advance from the clinic to the children’s bedside.