Biology subjects

Nagaraju, G. P.

Publications and source records attributed to Nagaraju, G. P..

3 recordsLinked to original sources

bioRxiv2026

ProAgio, a Novel Integrin αvβ3 Targeted Cytotoxin, Suppresses Tumor Growth and Reprograms the PDAC Microenvironment

BackgroundPancreatic ductal adenocarcinoma (PDAC) is characterized by a dense, hypoxic and immune-suppressive tumor microenvironment (TME). Integrin v{beta}3-expressing cells, including endothelial and cancer-associated fibroblasts (CAFs), contribute to the development of this TME. ProAgio is a novel cytotoxin that targets integrin v{beta}3-expressing cells. ProAgio is currently in clinical trials. We have previously shown that the combination of GPH (gemcitabine, paricalcitol, and hydroxychloroquine) influences PDAC TME. Based on the overlapping mechanisms of action, we hypothesized that ProAgio could potentiate effects of GPH and enhance its anti-tumor immunity. MethodsPatient-derived xenograft (PDX) and orthotopic models of PDAC were used to assess the therapeutic activity and mechanism of action of ProAgio in combination with GPH. Immunohistochemistry was used to evaluate hypoxia, EMT and angiogenesis. Changes in the immune cells were measured with multi-parameter flow cytometry. Dynamic contrast-enhanced MRI (DCE-MRI) was used to study tumor perfusion in mice and patients (NCT06182072). FindingsProAgio potentiated the growth inhibitory effects of GPH in PDX and orthotopic models by depleting integrin {beta}3 expressing cells, leading to ECM remodeling, reduced vascular leakage, improved hypoxia, and reversed EMT. DCE-MRI showed a significant increase in tumor perfusion following ProAgio treatment in mice and patients (NCT06182072). Immune profiling revealed that the combination treatment significantly increased the infiltration of {gamma}{delta} T cells, natural killer T (NKT) cells, CD4+ effector T cells, and M1-like macrophages. Furthermore, the combination treatment reduced the expression of myofibroblastic CAFs (myCAFs), further supporting the immunomodulatory and stromal normalizing effects of GPH and ProAgio. ConclusionTargeting integrin v{beta}3 using ProAgio modulates the PDAC TME by improving perfusion, reducing hypoxia, reversing EMT, and alleviating immune suppression. ProAgio potentiates the effects of GPH therapy, which should be evaluated in future trials.

cancer biology↗

bioRxiv2023

Novel Pan-RAS Inhibitor ADT-007 Induces Tumor Regression in Mouse Models of GI Cancer

Here, we describe a novel pan-RAS inhibitor, ADT-007, that potently inhibited the growth of RAS mutant cancer cells irrespective of the RAS mutation or isozyme. RASWT cancer cells with GTP-activated RAS from upstream mutations were equally sensitive. Conversely, RASWT cancer cells harboring downstream BRAF mutations and normal cells were essentially insensitive to ADT-007. Sensitivity of cancer cells to ADT-007 required activated RAS and dependence on RAS for proliferation, while insensitivity was attributed to metabolic deactivation by UDP-glucuronosyltransferases expressed in RASWT and normal cells but repressed in RAS mutant cancer cells. ADT-007 binds nucleotide-free RAS to block GTP activation of effector interactions and MAPK/AKT signaling, resulting in mitotic arrest and apoptosis. ADT-007 displayed unique advantages over mutant-specific KRAS and pan-KRAS inhibitors, as well as other pan-RAS inhibitors that could impact in vivo antitumor efficacy by escaping compensatory mechanisms leading to resistance. Local administration of ADT-007 showed robust antitumor activity in syngeneic immune-competent and xenogeneic immune-deficient mouse models of colorectal and pancreatic cancer. The antitumor activity of ADT-007 was associated with the suppression of MAPK signaling and activation of innate and adaptive immunity in the tumor immune microenvironment. Oral administration of ADT-007 prodrug also inhibited tumor growth, supporting further development of this novel class of pan-RAS inhibitors for RAS-driven cancers. SIGNIFICANCEADT-007 has unique pharmacological properties with distinct advantages over other RAS inhibitors by circumventing resistance and activating antitumor immunity. ADT-007 prodrugs and analogs with oral bioavailability warrant further development for RAS-driven cancers.

cancer biology↗

bioRxiv2022

Retrotransposons facilitates tissue specific horizontal Transfer of circulating tumor DNA

A variety of organisms have been shown to have altered physiology or developed pathology due to gene transfer, but mammals have never been shown to do so. Here, we show that circulating tumor DNA (ct) can promote cell-specific horizontal gene transfer (HGT) between human cancer cells and explain the mechanisms behind this phenomenon. Once ctDNA enters the host cell, it migrates to the nucleus and integrates into the cells genome, thereby transferring its genetic information. We determine that retrotransposons of the ERVL, SINE, and LINE families are necessary for cell targeting and the integration of ctDNA into host DNA. Using chemically synthesized retrotransposons, we found that AluSp and MER11C reproduced multiple myelomas (MM) ctDNAs cell targeting and integration into MM cells. We also discovered that ctDNA might, as a result of HGT, influence the treatment response of multiple myeloma and pancreatic cancer models. Overall, this is the first study to show that retrotransposon-directed HGT can promote genetic material transfer in cancer. There is, however, a broader impact of our findings than just cancer since cell-free DNA has also been found in physiological and other pathological conditions as well. Furthermore, with the discovery of transposons-mediated tissue-specific targeting, a new avenue for the delivery of genes and therapies will emerge.

cancer biology↗