New Studies Reveal Promising Cancer Targets and Treatment Strategies

In a wave of new cancer research, scientists have reported advances ranging from a druggable target that strips tumors of their immune-evading protective coating to a self-assembling antibody-drug conjugate that attacks multiple cancer targets at once. The findings, published across several journals, also include a new protein structure that could guide BRAF-targeted drug design and a discovery that may explain the origins of a rare childhood blood cancer.

Researchers at Washington University School of Medicine in St. Louis have shown in mice that it is possible to increase the potential effectiveness of antibody-drug conjugates (ADCs), a relatively new class of cancer medication often given to patients for whom standard chemotherapy has not worked. By modifying such drugs already approved by the U.S. Food and Drug Administration so that they self-assemble in the body and attack more than one cancer target, the researchers dramatically improved the effectiveness of these medications. The study was published July 15 in Nature. ADCs combine three components: a cytotoxic drug that kills a cancer cell, an antibody protein that binds to receptors unique to cancer cells, and a linking molecule. Because each drug can be attached to only one antibody partner, these conjugates attack only one kind of target at a time, limiting their effectiveness against tumors with multiple types of targets. Using click chemistry, the team created a self-assembling drug apparatus that could tack on a second antibody, doubling the receptor types it could bind to. Both antibodies used in the study are FDA-approved and target the EGFR and HER2 receptors. In mice modeling pancreatic, gastric or breast cancer tumors, tumor cells took up much higher amounts of the modified antibody-drug conjugates than typical, and survival improved significantly — as much as 90% of the animals survived 120 days after treatment in the pancreatic model.

A separate team led by researchers at The University of Texas at Austin report in the journal Nature Chemical Biology that they have found a completely different approach to attacking cancer metabolism. Instead of starving cancer cells, the experimental drug tricks them into consuming even more sugar than usual while simultaneously blocking their backup fuel source — fat. By attacking both fuel sources at once, the drug puts cancer cells under extreme stress and kills many of them. In lab experiments, the drug was effective against several types of human cancer cells, including melanoma, leukemia, breast cancer, lung cancer, liver cancer and neuroblastoma. In mice with an aggressive form of melanoma, most cancer cells died while non-cancerous cells were much less affected. The drug has two parts: a targeting agent, a molecule called XJ-4-85, acts on an enzyme called PFKL, speeding up glycolysis, and then releases a payload that acts on another enzyme, CPT2, disrupting fatty acid breakdown. The researchers describe the compound as a fully chemical counterpart to antibody-drug conjugates, which they call "electrophile-drug conjugates" (EDCs). The research is still in its early stages; much more laboratory testing is needed before the drug can be studied in people.

Scientists have also identified a promising therapeutic target that could disrupt the protective layer of sugar-derived molecules cancer cells use to evade the immune system. Results published in Science Advances show that, under conditions of hyperglycemia, the HSF1 protein is essential for building this "invisibility cloak." Researchers found that both the stiffness of the tumor microenvironment and glucose levels can alter the thickness of the protective coating, known as the glycocalyx. Under hyperglycemia, elevated levels of HSF1 were observed, and further experiments showed that cancer cells could only boost their ability to evade the immune system when HSF1 was present in conditions mimicking the tumor microenvironment. These findings point to a potential therapeutic opportunity to develop drugs that target HSF1 to thin the glycocalyx and make cancer cells more visible to the immune system.

Researchers at the Paul Scherrer Institute PSI and the University of Zurich have resolved a previously unknown conformation adopted by the BRAF protein during cell proliferation, opening new avenues for cancer treatment. Around half of melanomas and about seven percent of all other cancers carry a mutation in BRAF, which disrupts regulation of cell division and drives uncontrolled tumor growth. The researchers discovered a previously unknown asymmetric BRAF dimer that forms during the signaling cascade, in which the NtA sequence of one BRAF extends toward its partner to form a kind of bridge. They produced for the first time a high-resolution visualisation of the exact structure of this complex in its active form, consisting of the two BRAF proteins linked asymmetrically via NtA and the MEK1 protein. "The more precisely we know the structure of these components, the more precisely we can design drugs that fit perfectly," the researchers stated. They are already searching for molecules that bind to the newly characterised BRAF-MEK1 complex and could interrupt the unwanted signaling.

Targeted dendritic cell vaccines are also emerging as a major step forward in cancer immunotherapy, according to a review in Genes & Diseases. These therapies are engineered to carry tumor-associated antigens, enabling the immune system to identify cancer cells and stimulate cytotoxic T lymphocytes to trigger a focused attack on malignant cells while sparing healthy tissue. Current strategies incorporate genetic modification, mRNA delivery systems, and cell fusion techniques; fusion-based vaccines combine dendritic cells with tumor cells, creating hybrid structures capable of presenting a broad spectrum of cancer markers. When paired with chemotherapy, immune checkpoint inhibitors, or engineered T-cell therapies, these vaccines can amplify immune activation and help overcome tumor-induced immunosuppression. Emerging innovations include natural dendritic cell subsets and cell-free exosome-based vaccines.

In research on rare childhood blood cancer, investigators in Italy funded by Curestarters have uncovered for the first time the process the body uses to create blood cells before birth. The discovery could help expose the causes of juvenile myelomonocytic leukaemia (JMML), a rare childhood blood cancer that accounts for 1% of all paediatric leukaemias and about 1-2 cases per million people. Historically, survival rates for JMML have been poor, with 90% of patients dying from the disease; with the development of bone marrow transplants this number has improved to 50%. The researchers believe the discovery provides the groundwork to fully understand the origins of blood cancers and to develop better, more targeted treatments.

Cachexia, a cancer-linked syndrome that causes reduced appetite and muscle wasting, has also become a focus of major research efforts. Between 50% and 80% of people with cancer experience cachexia, depending on tumor type and disease stage, and 20–30% of cancer-associated deaths are attributable to cachexia rather than the cancer itself. There are no approved medications for cancer cachexia in most parts of the world; the appetite stimulant anamorelin is available in Japan, but the U.S. Food and Drug Administration and the European Medicines Agency found the evidence for its benefits to be insufficient for approval. In 2020, Cancer Grand Challenges funded an international team of 16 research groups across 14 institutions, known as CANCAN, with £20 million ($25 million) to study cancer cachexia. Now in its fifth year, the project has released about 30 papers, and a handful of companies, including Pfizer, are testing medicines for cachexia.