In a compelling series of recent breakthroughs, scientists at City of Hope have illuminated promising new paths for tackling some of the most intractable forms of cancer. Their multi-faceted approach includes deciphering molecular mechanisms behind drug resistance in acute myeloid leukemia, uncovering genetic disparities in triple-negative breast cancer among Black women, potentiate CAR T cell immunotherapies, pioneering novel treatments for glioblastoma using scorpion venom, and engineering viruses capable of breaching pancreatic tumor defenses. Collectively, these advances underscore a visionary commitment to revolutionizing cancer therapy through cutting-edge research.
Central to the challenge of treatment resistance in acute myeloid leukemia (AML) is the enigmatic role of the protein ALKBH1, as meticulously detailed by Dr. Jianjun Chen and his team. AML cells exploit a phenomenon known as codon-biased translation, enabling the preferential production of tumor-supportive proteins. ALKBH1 emerges as a key orchestrator in this process by remodeling the architecture of mitochondria, the cell’s energy hubs. This remodeling optimizes mitochondrial efficiency, supplying leukemia cells with an energetic advantage that bolsters survival and adaptation against targeted therapies like venetoclax. Experimental inhibition of ALKBH1, especially in concert with venetoclax treatment, yielded significant anti-leukemic effects with minimal toxicity in preclinical models, highlighting a promising therapeutic axis that could overcome refractory AML and perhaps other ALKBH1-driven malignancies.
Turning to breast cancer, researchers led by Dr. John Carpten have delivered an unprecedented genomic landscape analysis of triple-negative breast cancer (TNBC) in Black women. This aggressive subtype, characterized by the absence of estrogen, progesterone, and HER2 receptors, disproportionately affects younger African American women with poorer prognosis. By sequencing tumor genomes from over four hundred Black women, the study disclosed distinctive mutational patterns, notably a higher frequency of TP53 mutations and a lower prevalence of PIK3CA mutations compared to other populations. Notably, the tumors segregated into two distinct genomic subtypes with divergent clinical trajectories—one associated with younger age and better survival marked by a robust mutational burden, and another linked to older age, elevated body mass index, attenuated immune responses, and poorer outcomes. These findings not only provide crucial insights into the molecular underpinnings of racial disparities in TNBC but also point towards tailored immunotherapeutic and targeted intervention strategies that could enhance survival in this underserved demographic.
Immunotherapy innovation took a leap forward with research into Th9 cells, a subset of helper T cells endowed with formidable anti-tumor activity. The City of Hope team, including Drs. Michael Caligiuri and Shoubao Ma, dissected the molecular brakes imposed by YTHDF2, an RNA-binding protein that regulates the development and function of Th9 cells. By genetically removing YTHDF2, they unleashed a proliferation of hyperactive Th9 cells exhibiting enhanced tumor-killing capabilities. This revelation opens new avenues for CAR T cell engineering, where reprogrammed Th9 cells can be harnessed to confront solid tumors—long considered impregnable by traditional CAR T therapies. Such enhancements could dramatically expand the reach and potency of cellular immunotherapeutics.
In a striking and unconventional pivot, City of Hope scientists have developed a CAR T cell therapy for glioblastoma that incorporates chlorotoxin, a peptide derived from scorpion venom, to target malignant brain tumors with precision. This innovative approach, pioneered by neurosurgeon Dr. Behnam Badie and colleagues, exploits chlorotoxin’s natural affinity for glioblastoma cell membranes without harming normal brain tissue. Early-phase clinical trials demonstrated safety and tolerability, with CAR T cells persisting in the tumor microenvironment and achieving temporary disease stabilization in most patients despite the aggressive nature of glioblastoma. This pioneering work embodies a fusion of natural toxin biology and synthetic immunotherapy, offering renewed hope against one of the deadliest cancers known.
Further advancing the fight against recalcitrant tumors, City of Hope researchers engineered an oncolytic virus named CF33-hNIS-antiPDL1 designed to infiltrate and dismantle the immunosuppressive microenvironment of pancreatic ductal adenocarcinoma (PDAC). This virus not only selectively infects and lyses pancreatic cancer cells but also expresses a checkpoint inhibitor targeting PD-L1, a protein that tumors exploit to evade immune detection. In preclinical models, this dual-action viral therapy significantly curtailed tumor growth, enhanced immune cell infiltration, and prolonged survival. Notably, intraperitoneal administration of CF33-hNIS-antiPDL1 yielded superior efficacy over systemic delivery, highlighting the importance of delivery routes in virotherapy. These findings propel CF33 derivatives as potent candidates in the quest to breach pancreatic cancer’s formidable immune defenses.
Together, these advances epitomize the sophisticated convergence of molecular biology, genomic medicine, immunoengineering, and virotherapy in contemporary oncology research. City of Hope’s integrated model—from deep mechanistic studies, through translational preclinical evaluation, to pioneering clinical trials—embodies a paradigm shift towards personalized, multi-dimensional cancer care. The elucidation of ALKBH1’s mitochondrial modulation in AML enriches the therapeutic arsenal against drug resistance, while the human genomic insights into TNBC highlight the critical need to address racial disparities with precision medicine. CAR T cell evolutionary leaps through Th9 enhancement and venom-based targeting redefine immunotherapy’s potential against formidable solid tumors. Lastly, the marriage of viral engineering and checkpoint blockade holds promise to transform the grim landscape of pancreatic cancer prognosis.
These breakthroughs, supported by national and international collaborations, including licensing partnerships with biotechnology firms, reaffirm City of Hope’s status as a beacon of innovation in cancer research. Ensuring equitable access to these therapies and continued inclusion of diverse populations in clinical studies remain imperative. As these novel strategies progress from bench to bedside, they embody a collective promise to redefine cancer survivorship and ultimately translate scientific insight into lasting hope for patients worldwide.
Subject of Research: Acute Myeloid Leukemia, Triple-negative Breast Cancer, CAR T Cell Therapy, Glioblastoma, Pancreatic Cancer
Article Title: City of Hope Unveils Molecular and Therapeutic Innovations to Combat Resistant Cancers
News Publication Date: Not specified
Web References:
– https://www.cityofhope.org/
– https://aacrjournals.org/cancerdiscovery/article/10.1158/2159-8290.CD-24-1043/763931/ALKBH1-drives-tumorigenesis-and-drug-resistance
– https://www.nature.com/articles/s41588-025-02322-y
– https://www.nature.com/articles/s41590-025-02235-2
– https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00375-1
– https://www.sciencedirect.com/science/article/pii/S075333222500602X
References:
– Chen, J. et al. ALKBH1 Drives Tumorigenesis and Drug Resistance in AML. Cancer Discovery.
– Carpten, J. et al. Genomic Landscape and Distinct Subtypes of Triple-Negative Breast Cancer in Black Women. Nature Genetics.
– Caligiuri, M., Ma, S. YTHDF2 Regulates Th9 Cell Development and Enhances CAR T Immunotherapy. Nature Immunology.
– Badie, B., Barish, M., Brown, C. CLTX-CAR T Cells for Glioblastoma: Early Clinical Trial Outcomes. Cell Reports Medicine.
– Woo, Y. et al. CF33 Oncolytic Virus Engineered to Block PD-L1 in Pancreatic Cancer. Biomedicine & Pharmacotherapy.
Image Credits: City of Hope
Keywords: Myeloid leukemia, Triple-negative breast cancer, CAR T therapy, Glioblastoma, Pancreatic cancer, ALKBH1, TP53 mutation, YTHDF2, Chlorotoxin, Oncolytic virus, Immune checkpoint blockade, Cancer drug resistance
