German Cancer Research Center

According to the recent announcement on the CDE (China's Center for Drug Evaluation) website, Bayer has successfully obtained clinical trial approvals for two of its novel Class 1 drugs, which are aimed at addressing the treatment needs of patients with late-stage solid tumors and acute ischemic stroke.   Based on Bayer's public information, one of the new drugs is a DGKα inhibitor, and the other is a protein-based drug targeting α2AP. These two candidates are currently in Phase 1 and Phase 2 clinical development stages, respectively, at the international level.   BAY 2862789 oral solution, a small-molecule DGKα inhibitor co-developed by Bayer and the German Cancer Research Center (DKFZ), is now undergoing the first-in-human Phase 1 clinical trial globally. Its research and development target is the treatment of solid tumors. The diacylglycerol kinase (DGK) family plays a crucial role in the development, differentiation, and functional regulation of T cells and NK cells, with DGKα and DGKζ being the predominant isoforms. Studies have shown that DGKα is significantly expressed in various refractory cancers, promoting cell proliferation and inhibiting apoptosis. Its high expression is closely related to T-cell exhaustion, which is a key factor in the evasion of immune surveillance by late-stage cancers. Therefore, the specific inhibition of DGKα holds great potential in the field of cancer therapy, as it can effectively suppress cancer cell proliferation and activate T-cell functions, achieving a dual anti-cancer effect. Furthermore, the synergistic effect of this inhibitor with PD-1/PD-L1 inhibitors offers new hope for the treatment of refractory cancers.   The other new drug, BAY 3018250, is a protein-based drug targeting α2AP, which is part of Bayer's cardiovascular disease research and development pipeline. It aims to treat acute ischemic stroke and pulmonary embolism. Currently, this drug has made significant progress in the international Phase 2 clinical trial for the treatment of deep vein thrombosis (DVT). DVT is a serious health issue that can lead to life-threatening blockage of blood flow in the lungs. BAY 3018250 exerts its therapeutic effect by dissolving blood clots. Thrombotic vascular occlusion is a key factor in the development of ischemic stroke, and α2-antiplasmin (α2AP), a member of the serine protease inhibitor family, is closely associated with an increased risk of ischemic stroke and the failure of recombinant tissue plasminogen activator (rt-PA) treatment. Research has shown that anti-α2AP therapy can significantly reduce the formation of microvascular thrombosis, ischemic brain injury, brain edema, intracerebral hemorrhage, and mortality after ischemic stroke, suggesting that the temporary inactivation of α2AP may have potential therapeutic value for ischemic stroke. With the approval for clinical trials in China, BAY 3018250 will now be evaluated for the specific indication of acute ischemic stroke, bringing new hope for the treatment of this condition.

Cancer genomes are the result of diverse mutation processes that have often accumulated over decades. Scientists have analyzed the molecular evolution of tumors after exposure to mutagenic chemicals. DNA lesions that persists unrepaired over several cell generations lead to sequence variations at the site of damage, the quantification of which provides insights into the kinetics and mechanisms of DNA repair. This enabled the researchers to distinguish the contribution of the triggering lesion from that of the subsequent repair in shaping the mutation pattern. Cancer genomes are the result of diverse mutation processes that have often accumulated over decades. Scientists from the German Cancer Research Center (DKFZ) and the Universities of Cambridge and Edinburgh have analyzed the molecular evolution of tumors after exposure to mutagenic chemicals. DNA lesions that persists unrepaired over several cell generations lead to sequence variations at the site of damage, the quantification of which provides insights into the kinetics and mechanisms of DNA repair. This enabled the researchers to distinguish the contribution of the triggering lesion from that of the subsequent repair in shaping the mutation pattern. These results have now been published in the journal Nature. After DNA damage, for example by chemicals, the damaged and undamaged DNA strands are separated from each other during cell division. The cells often do not repair the DNA damage immediately; the lesions persist over several rounds of cell division. The damaged DNA can be copied by specialized enzymes known as translesion polymerases. However, these enzymes incorporate DNA building blocks (nucleotides) at random or simply skip the damaged nucleotide. The daughter cells develop different mutation profiles as a result. Researchers refer to this as "lesion segregation." This results in complex mutation patterns in a clonal cell population such as a tumor, and can reveal which damaged DNA strand a cancer cell inherited from its "ancestors." Researchers led by Duncan Odom, DKFZ, Sarah Aitken, University of Cambridge and Martin Taylor, University of Edinburgh, investigated the question of how this asymmetry of DNA damage and DNA repair comes about. In particular, they wanted to clarify whether it plays a role in the mutation rate which of the two DNA strands is damaged. Despite the symmetry of both strands of the DNA ladder, they differ in many respects: only one of the strands is read into RNA, different machinery copies each of the two strands during replication, and both strands are differently accessible to repair enzymes. The team used a mouse model to investigate how diethylnitrosamine damages liver cells and ultimately causes liver cancer. The substance damages the genetic material by chemically bonding with a base. Experts refer to such stable attachments as small DNA adducts. For their current study, the researchers examined 237 tumors from 98 mice and analyzed over seven million mutations. Contrary to expectations, they found no significant differences in the mutation rates of the two strands of DNA (leading and lagging strand) despite their replication being performed by different processes. They went on to show that on encountering damage, both processes recruit the same damage bypass machinery with the same efficiency. This stands in stark contrast to the asymmetric strand tolerance of the much more space-consuming UV light-induced adducts and gives new insight into how cells deal with the DNA damage caused by smoking and cancer treatments. The accumulation of several different mutations at the site of persistently unrepaired DNA lesions can be used to measure the efficiency of repair processes -- in the entire genome and with a resolution of single nucleotides. The researchers found that the mutations induced by DNA damage are largely shaped by the influence of DNA accessibility on repair efficiency rather than where damage occurs. Finally, they reveal specific genomic conditions that actively drive cancer-promoting mutagenesis by impairing the reliability of a specific repair mechanism called "nucleotide excision repair." Duncan Odom, one of the senior authors of the study, summarizes: "Our results shed light on how strand-asymmetric mechanisms of DNA damage generation, tolerance and repair underlie the evolution of the cancer genome."

WEDNESDAY, June 5, 2024 -- Lowering the fecal immunochemical test (FIT) positive threshold yields levels of sensitivity and specificity that are comparable to those reported for multitarget stool RNA (mt-sRNA) testing without the additional testing, according to a research letter published online June 1 in the Journal of the American Medical Association . Tobias Niedermaier, Ph.D., from the German Cancer Research Center in Heidelberg, and colleagues examined whether lowering the FIT positivity threshold could achieve levels of sensitivity and specificity comparable to mt-sRNA testing, which incorporates a commercially available FIT, concentration of eight RNA transcripts, and participant-reported smoking status, without additional stool testing and smoking assessment. The sensitivities of FIT for detecting colorectal cancer (CRC) or advanced adenoma and specificity for absence of advanced neoplasia were ascertained for FIT in the BLITZ study after lowering the positivity threshold to 8.8 µg/g, which yielded the same positivity rate as reported for the mt-sRNA test in the CRC-PREVENT study (17 percent). A total of 7,607 participants were included in the analyses. The researchers found that lowering the FIT positivity threshold achieved similar sensitivities for CRC (94.9 versus 94.4 percent) and for advanced adenoma (44.7 versus 45.9 percent). Specificities were also similar (86.9 versus 85.5 percent). "Future comparisons of novel stool-based screening tests with FITs should incorporate comparisons of sensitivities at the same positivity rate or specificity," the authors write. Abstract/Full Text Whatever your topic of interest, subscribe to our newsletters to get the best of Drugs.com in your inbox.