Specific co-mutations in KRAS-mutant NSCLC improve treatment response
Read summary | Read in Cancer Cell
Patients with KRAS-mutant non-small cell lung cancer (NSCLC) also often have co-mutations in KEAP1 and LKB1, which are associated with problems with DNA damage repair pathways, treatment resistance and reduced survival. Targeting the two main components in the DNA damage repair pathway using ATR inhibitors has emerged as a therapeutic strategy, but there currently are no biomarkers to determine which patients with NSCLC are likely to benefit. To provide insights, researchers led by John Heymach, M.D., Ph.D., examined the role of KEAP1 and LKB1 co-mutations on ATR inhibitor response in NSCLC tumors. These co-mutations were associated with enhanced response to ATR inhibitors both in vitro and in vivo. Moreover, adding immune checkpoint blockade or chemotherapy in combination with ATR inhibitors further improved antitumor activity. These results suggest that these co-mutations could be potential predictive biomarkers for ATR inhibitor response in patients with NSCLC.
Chemotherapy drives changes to the genome and clonal architecture of blood stem cells that may increase risk of secondary malignancies
Read summary | Read in Nature Genetics
Hematopoietic stem and progenitor cells (HSPCs) – a main source of blood cell production – can accumulate DNA mutations over time, which can be influenced by various external stressors. However, it is unclear how chemotherapy in patients with cancer affects mutations in their normal HSPCs. To provide insights, researchers led by Koichi Takahashi, M.D., Ph.D., conducted whole-genome sequencing on 1,276 single-cell-derived HSPCs from 10 previously-treated patients with multiple myeloma. They characterized the effects of several chemotherapy drugs, including melphalan, which increased the risk of developing certain mutations. The researchers also found that chemotherapy accelerated the remodeling of HSPCs, leading to a reduction in their clonal diversity. This research suggests that chemotherapy can accelerate the development of mutations that could increase the risk for later leukemia, which may help researchers to better understand these risks and develop interventions to prevent chemotherapy-related secondary cancers.
New-onset diabetes may serve as an early marker of pancreatic cancer
Read summary | Read in Gastroenterology
Pancreatic cancer screening is not recommended for the general population due to its low incidence, leading to later diagnoses after symptoms already have appeared at an advanced stage. Studies show that one-fifth of patients with pancreatic cancer develop new-onset diabetes (NOD), suggesting a higher risk. To provide insights into the risk of developing pancreatic cancer following NOD, Suresh T Chari, M.D., and colleagues prospectively identified 18,838 adults with NOD and followed them for diagnosis of pancreatic cancer. One in 160 patients with NOD were diagnosed with pancreatic cancer within three years. Interestingly, most patients were diagnosed within the first year, suggesting that the cancer causes diabetes. The study also highlighted racial and ethnic differences, with white adults having the highest rate of pancreatic cancer after NOD. This large prospective study confirms the correlation between NOD and pancreatic cancer, suggesting NOD as a potential marker for earlier detection of pancreatic cancer.
Novel agent restores p53 function in p53-mutated AML
Read summary | Read in Blood
Mutations of the TP53 gene are very common in leukemias and other cancers. They are predictors of poor response to therapies and are also associated with poor survival. To address this, Bing Carter, Ph.D., Michael Andreeff, M.D., Ph.D., and colleagues investigated the first agent specifically targeting a p53 mutant protein made by a unique TP53 mutation called Y220C in leukemias. The agent, rezatapopt, partially restores the normal function of the mutant p53 protein. Researchers discovered that two other proteins block the antitumor power of rezatapopt and, further, that the reactivated p53 does not bind to pro-survival BCL-2 proteins as normal p53 does. Combinations of rezatapopt along with inhibitors of these other proteins induced strong cancer cell death and improved survival in vivo. A clinical trial is underway to examine this strategy in patients, offering the first tailored approach to fighting a specific TP53 mutation in acute myeloid leukemia (AML).
Study uncovers target to overcome resistance in ARID1A-mutant cancers
Read summary | Read in Cancer Research
Many ovarian clear cell carcinomas (OCCCs) have mutations that inactivate the ARID1A tumor suppressor and are associated with resistance to standard treatments and poor patient prognoses. To provide insights into the underlying mechanisms, researchers led by Rugang Zhang, Ph.D., examined ARID1A-mutant OCCC cells. They found that ARID1A mutations create a dependence on the alanine amino acid through regulating alanine transporter proteins including SLC38A2, which acts as a gatekeeper to support rapid cancer growth. Inhibiting SLC38A2 led to reduced alanine, slowed cell growth and tumor shrinkage. Additionally, SLC38A2 inhibition enhanced the activity of immune checkpoint blockade in vivo and chimeric antigen receptor (CAR) T therapy in vitro. These results suggest that targeting alanine transport alone or in combination with immunotherapy is a promising therapeutic strategy for ARID1A-mutant cancers.
Study uncovers potential therapeutic targets for low platelet blood disorders
Read summary | Read in Nature Communications
Thrombocytopenia is a blood disorder characterized by low levels of blood platelets. These tiny blood cells, which help with clotting, are made in the bone marrow and spleen by cells called megakaryocytes. However, little is known about the regulatory factors involved in platelet formation, which could be used to develop more effective therapeutic strategies for thrombocytopenia. MLL3 and MLL4 are part of a protein complex that modifies histones involved in DNA packaging to control gene activity. Both genes are frequently mutated in various cancer types, leading Margarida Santos, Ph.D., and colleagues to examine their role in platelet formation. The researchers generated models missing the MLL3 and MLL4 genes. They found models missing only one gene had normal platelet counts, but those missing both had impaired megakaryocyte maturation and developed severe macrothrombocytopenia, with fewer and larger-than-normal platelets that easily self-destruct. These results provide epigenetic insights into blood disorders involving low platelets, highlighting MLL3 and MLL4 as potential therapeutic targets.
Combining immunotherapy with bacterial injection shows promise in treatment-refractory solid tumors
Read summary | Read in Clinical Cancer Research
Solid tumors contain areas with low oxygen levels, known as hypoxic regions, that are associated with treatment resistance, aggressive growth and an increased risk of metastasis. In previous studies, injecting tumors with Clostridium novyi-NT, a non-toxic bacteria species that thrives in hypoxic environments, can trigger an antitumor response. A new Phase Ib trial led by Sarina Piha-Paul, M.D., combined this approach with intravenous (IV) pembrolizumab immunotherapy treatment. Adding IV immunotherapy amplified the bacteria’s ability to destroy cells, boosting the T cell-mediated immune response. Of 16 patients, four had partial responses, with one having a complete response. The median duration of response was 10.9 months, and stable disease was observed in 69% of the patients. While there was one grade three dose-limiting toxicity, all other adverse effects seen in more than 10% of patients were localized and manageable. These results highlight the therapeutic potential of this combination for patients with treatment-refractory solid tumors.
Honors and Awards
Clifton Fuller, M.D., Ph.D., Melissa Joyner, M.D., and Steven Lin, M.D., Ph.D., professors of Radiation Oncology, and Narayan Sahoo, Ph.D., professor of Radiation Physics, were inducted into the 2025 Class of Fellows of the American Society for Radiation Oncology (ASTRO) Jackie Broadway-Duren, Ph.D., of the Leukemia department, was inducted into the 2025 class of Fellows of the American Association of Nurse Practitioners (FAANP)
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