Exosomes, enriched with cancer-specific nucleic acids and proteins, have emerged as key intercellular communicators for orchestrating a tripartite axis of the tumor microenvironment (TME). They contribute significantly to tumor progression, particularly through their involvement in drug resistance, immune suppression, and metastasis. Recently, extensive research has mapped isolated functions to integrated perspective on how exosomal cargo mediates the complex crosstalk between these three important avenues of tumor survival. This begins by outlining the fundamental mechanisms of exosome biogenesis, cargo sorting and release that are frequently hijacked by cancer cells. This review then examines the exosome-mediated transfer of drug efflux pumps, non-coding RNAs, and metabolic enzymes from drug-resistant tumor cells to drug-sensitive cells. Subsequently, this review explore how tumor derived exosomes influence the premetastatic niche to support angiogenesis, including the horizontal transfer of key cytokines and growth factors. Additionally, this review details the role of tumor derived exosomes in shaping an immunosuppressive TME, especially their capacity to modulate T-cell function, polarize myeloid cells, and influence immune checkpoint signalling. Finally , we discuss emerging therapeutic strategies aimed at intercepting or reprogramming exosomal cargo to potentially prevent metastasis, sensitize tumor to therapeutics , and counteract immune evasion. By shifting the focus from isolated mechanisms to the interconnected roles of exosomes, this review aims to inform the rational design of next-generation exosome targeted and exosome based cancer therapeutics.
RamaRao Malla, G. P. Nagaraju· Biochemical Pharmacology· 0 citations
Multiple cancers arise from co-occurring mutations that activate RAS/MAPK and Wnt/β-catenin signaling pathways, which cooperate to drive tumorigenesis, metastasis, and drug resistance. A dual inhibitor of RAS and β-catenin signaling may offer a more effective therapeutic strategy compared with monospecific inhibitors of RAS or β-catenin currently in clinical trials for such cancers. We previously reported that the cGMP-degrading phosphodiesterase 10A (PDE10) isozyme is overexpressed in various cancers and that pharmacological inhibition or genetic silencing of PDE10 selectively suppresses the growth of cancer cells with high PDE10 expression relative to normal cells with low PDE10 levels. Because conventional PDE10 inhibitors developed for CNS disorders are rapidly metabolized and cause sedation, we developed ADT-030, a PDE10 inhibitor optimized for systemic bioavailability. ADT-030 potently inhibited recombinant PDE10 at concentrations that bind PDE10 in cells. Similar concentrations activated cGMP-dependent PKG, phosphorylated and degraded the oncogenic pool of β-catenin, and suppressed EGF-stimulated RAS-mediated MAPK/AKT signaling, resulting in mitotic arrest and apoptosis. Notably, cancer cells that developed cross-resistance to pan-RAS, pan-KRAS, and mutant-specific KRAS inhibitors retained full sensitivity to ADT-030. Oral administration of ADT-030 demonstrated robust antitumor activity across multiple mouse tumor models (orthotopic, xenograft, PDX, and chemically induced) and cancer types. KRAS-mutant pancreatic and lung cancer models were particularly sensitive to ADT-030, resulting in tumor regression, metastasis inhibition, and durable efficacy that persisted well beyond the treatment period. ADT-030 also inhibited tumor growth in a PDX model of adrenocortical carcinoma, a cancer driven by CTNNB1 mutations. Deep immunophenotyping studies revealed a significant impact of ADT-030 treatment on the tumor immune microenvironment, characterized by selective induction of apoptosis in MDSC cells and increased tumor infiltration by CD8+ T cells and NK cells. The activity of ADT-030 was comparable to that of chemotherapy and immune checkpoint inhibitors, while combinations showed greater efficacy. These results support IND-enabling studies of ADT-030 as a monotherapy or in combination with standard-of-care treatments for patients with a broad range of RAS-driven cancers, and especially for patients who relapsed after RAS inhibitor treatment. Because PDE10 has low expression and no known physiological function outside the CNS, ADT-030 is not expected to cause on-target toxicities associated with monospecific RAS or β-catenin inhibitors.
Xi Chen, Dhana S.R. Bandi, Ganji P. Nagaraju, Junwei Wang, Sindhu Ramesh, Kristy L. Berry, Khalda Fadlalla, Elmar Nurmemmedov, Ivan Babic, Gang Zhou, Fokhrul Hossain, Suresh Kumar, Nitin Roper, Jeremy B. Foote, Donald J. Buchsbaum, Adam B. Keeton, Yulia Y. Maxuitenko, Bassel F. El-Rayes, Gary A. Piazza. ADT-030, a novel PDE10 inhibitor that blocks RAS and β-catenin signaling with robust and durable antitumor activity and potential to mitigate resistance and on-target toxicities of monospecific RAS inhibitors [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B005.
Xi Chen, D. Bandi, G. P. Nagaraju et al.· Clinical Cancer Research· 0 citations
Breast cancer is the most frequently reported cancer in women, with high mortality and morbidity globally. Paclitaxel, doxorubicin, tamoxifen, cisplatin, and 5-fluorouracil are cornerstones of standard-of-care treatment for primary and advanced breast cancers, targeting distinct molecular mechanisms. However, the evolution of acquired resistance primarily leads to treatment failure and progression to metastasis, ultimately to patient mortality. Furthermore, their effectiveness is limited by potential toxicities in various organs. These limitations present an extreme challenge for the management of breast cancer at the advanced stage. This review uncovers recent updates on acquired resistance mechanisms toward standard-of-care treatments driven by deeply rooted heterogeneity and aggressive nature through direct counteracting of its core action, hyperactivation of survival pathways, silencing of core cell death pathways, derepressing the expression of multidrug resistance proteins, metabolic reprogramming, epigenetic modifications, and exosome-mediated horizontal transfer of resistance phenotype. In addition, we discuss recent updates on potential strategies to overcome resistance and toxicities induced by standard-of-care treatments. Ultimately, this review helps to identify novel strategies targeting pathways to reverse resistance and reduce toxicity in breast cancer patients.
Anuveda Sree Samudrala, G. P. Nagaraju, RamaRao Malla· Biochimica et biophysica act...· 0 citations
An orally bioavailable prodrug of ADT-1004, ADT-1004, demonstrated favorable tolerability and suppressed tumor growth in orthotopic and patient-derived xenograft models of pancreatic cancer, accompanied by reductions in activated RAS and p-ERK levels (Mol Cancer, 2025).
Junwei Wang, Xi Chen, Bandi D. S. Reddy et al.· Clinical Cancer Research· 0 citations
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