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Amanda Braga Bona

Carisma Therapeutics (United States)

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Paulo Pimentel de Assumpção

Universidade Federal do Pará

Rommel Mário Rodríguez Burbano

Universidade Federal do Pará

Helem Ferreira Ribeiro

Universidade da Amazônia

Danielle Queiroz Calcagno

Universidade Federal do Pará

Giovanny R. Pinto

Universidade Federal do Delta do Parnaíba

Nicholas G. Minutolo

Carisma Therapeutics (United States)

Karan Nagar

Carisma Therapeutics (United States)

Stefano Pierini

Carisma Therapeutics (United States)

Alison Worth

Carisma Therapeutics (United States)

Asen Bagashev

Children's Hospital of Philadelphia

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Carisma Therapeutics (United States)

Universidade Federal do Pará

University of Pennsylvania

Instituto Evandro Chagas

Universidade Federal de São Paulo

Universidade do Estado do Pará

Amazon Research Foundation

Centro Universitário de João Pessoa

Translational Therapeutics (United States)

Cancer Research Center

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The Emerging Role of miRNAs and Their Clinical Implication in Biliary Tract Cancer

Gastroenterology Research and Practice (2016)

Nina Nayara Ferreira Martins Kelly Cristina da Silva Oliveira Amanda Braga Bona Marı́lia de Arruda Cardoso Smith Geraldo Ishak

Biliary tract cancers are aggressive malignancies that include gallbladder cancer and tumors of intra- and extrahepatic ducts and have a poor prognosis. Surgical resection remains the main curative therapy. Nevertheless, numerous patients experience recurrence even after radical surgery. This scenario drives the research to identify biliary tract cancer biomarkers despite the limited progress that has been made. Recently, a large number of studies have demonstrated that deregulated expression of microRNAs is closely associated with cancer development and progression. In this review, we highlight the role and importance of microRNAs in biliary tract cancers with an emphasis on utilizing circulating microRNAs as potential biomarkers. Additionally, we report several single-nucleotide polymorphisms in microRNA genes that are associated with the susceptibility of biliary tract tumors.

Gallbladder Cancer

Biliary Tract Cancer

10.1155/2016/9797410

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Citations (6)

Genetic screening analysis of patients with hereditary diffuse gastric cancer from northern and northeastern Brazil

Hereditary Cancer in Clinical Practice (2014)

Caroline Aquino Moreira-Nunes Mariceli Baia Leão Barros Bárbara do Nascimento Borges Raquel Carvalho Montenegro Letícia Martins Lamarão

Hereditary diffuse gastric cancer (HDGC) is a hereditary autosomal inherited syndrome associated with CDH1 germline mutations. In Brazil, gastrointestinal tumors are among the most prevalent tumor types and constitute a serious public health problem, especially in the northern and northeastern regions. This study aimed to investigate germline mutations, methylation pattern and genomic rearrangements in the CDH1 gene and quantitative changes in the DNA of HDGC patients in northern and northeastern Brazil.Twenty-seven DNA samples from the members of four families affected by HDGC were analyzed using array comparative genomic hybridization (aCGH), DNA sequencing and methylation pattern.No evidence of gain and loss events or any rearrangements were found in any of the samples tested using aCGH. No promoter region hypermethylation was observed either. Two of the four families presented different types of germline mutations. The 185G > T and 1018A > G germline mutations detected in this study have been described in Asian and European families, respectively. The ancestors of the two families carrying these mutations had originated from those continents.This is the first study to evaluate CDH1 gene germline mutations in Brazilian families with HDGC. In our study, 50% of the families showed no CDH1 gene alterations, and it is possible that in regions with a high incidence of gastric cancer, such as northern and northeastern Brazil, environmental factors might have induced the different genetic alterations analyzed in this study.

CDH1

Comparative genomic hybridization

Human genetics

genomic DNA

10.1186/1897-4287-12-18

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Citations (24)

329 Pre-clinical efficacy of a novel anti-GPC3in vivoCAR-M for hepatocellular carcinoma

Regular and Young Investigator Award Abstracts (2024)

Asen Bagashev Vasso Pappa Amanda Braga Bona Kayleigh C. Ross Shuo Huang

Background

Chimeric antigen receptor macrophage (CAR-M) cell therapies have the potential to mediate robust anti-tumor immunity via phagocytosis, cytokine/chemokine release, antigen presentation, activation of the tumor microenvironment (TME) and T cell recruitment. Phase I data have demonstrated that autologous ex vivo CAR-M are well-tolerated, induce reprogramming of the solid TME, promote epitope spreading, and mediate anti-tumor activity.¹ Here, we have developed a novel off-the-shelf approach to directly reprogram endogenous myeloid cells in vivo by systemically delivering lipid nanoparticles (LNP) encapsulating mRNA encoding CARs targeting glypican-3 (GPC3). GPC3 is a tumor-associated surface antigen that is overexpressed in hepatocellular carcinoma (HCC) with minimal expression on normal tissues. The CAR architecture was optimized to maximize antigen-dependent myeloid activation.

Methods

Primary human monocytes and macrophages were used to assess binding, phagocytosis, killing, and cytokine release using flow cytometry, Incucyte^®-based cytotoxicity assays, and Meso Scale Discovery (MSD) or Nomic Bio based cytokine release assays. The efficacy and tolerability of CAR-encoding mRNA/LNP were evaluated in vivo in CD34+ humanized mice harboring GPC3+ solid tumor xenografts.

Results

In vitro analysis showed that anti-GPC3 CAR-M had a high binding affinity to GPC3, and lack of binding to related glypican proteins. A CAR comprising a hinge, transmembrane, and signaling domain optimized for myeloid cells demonstrated enhanced antigen-dependent macrophage activation without tonic signaling. Functional evaluation demonstrated CAR expression on human macrophages for more than 7 days in vitro leading to dose-dependent cytotoxicity against multiple GPC3+ tumor lines. At physiologic levels, soluble GPC3 did not interfere with the cytotoxic activity of anti-GPC3 CAR-M. In humanized immune system mice with disseminated GPC3+ solid tumors, systemic administration of anti-GPC3 CAR LNP/mRNA led to robust anti-tumor activity and suppressed tumor lesions in the liver. Myeloid cells were the primary CAR+ cells after systemic LNP administration. Treated animals tolerated repeat mRNA/LNP administration with no significant elevation in plasma cytokine levels or other signs of toxicity.

Conclusions

These data demonstrated that anti-GPC3 CAR-M can be directly produced in vivo utilizing mRNA/LNP, reducing tumor burden in translationally relevant humanized solid tumor models. In vivo CAR-M represents a novel off-the-shelf cell therapy strategy for patients with GPC3+ solid tumors, including HCC.

Reference

Abdou Y, Dees EC, Mortimer JE. A phase-1, first-in-human (FIH) study of autologous macrophages engineered to express an anti-HER2 chimeric antigen receptor (CAR) in participants (pts) with HER2-overexpressing solid tumors. J. Clin. Oncol. 2023;41:16 suppl.

10.1136/jitc-2024-sitc2024.0329

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Expression of hsa-miR-9 and MYC Copy Number Variation in Hereditary Diffuse Gastric Cancer

Anticancer Research (2017)

Kelly Cristina da Silva Oliveira Amanda Braga Bona FERNANDA JARDIM DA SILVA Thayanne Macedo Pinheiro Diego Di Felipe Ávila Alcântara

Approximately, 15-50% of families affected by hereditary diffuse gastric cancer (HDGC) exhibit CDH1 germline mutations. CDH1 gene encodes E-cadherin, protein essential to the cell-cell contact of gastric epithelium. Studies have shown that hsa-miR-9 participates in this protein downregulation. Moreover, MYC is responsible for the transcription of hsa-miR-9-3. In the present study, hsa-miR-9 expression and MYC copy number variation were investigated to elucidate the hsa-miR-9 role in HDGC.Tumor samples were obtained from nine individuals with HDGC history belonging to four Brazilian families. Then, relative quantification of hsa-miR-9 expression and MYC gene copy number variation analysis were performed by real-time PCR.In all the samples, an overexpression of hsa-miR-9 and an increased MYC copy number (≥3 copies) were observed.hsa-miR-9 acts as an oncomiR in HDGC. In addition, we suggest that hsa-miR-9 acts as second event in individuals with HDGC carrying CDH1 gene germinline mutations.

CDH1

10.21873/anticanres.11579

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Citations (5)

CDC25B Inhibition by Menadione: A Potential New Therapeutical Approach

Anti-Cancer Agents in Medicinal Chemistry (2022)

Helem Ferreira Ribeiro Carla de Castro Sant’ Anna Valdenira de Jesus Oliveira Kato Rafael Maia de Sousa Brasil Amanda Braga Bona

Gastric cancer (GC) is the fifth most common type of tumor and the third leading cause of cancer death worldwide. The evolution of gastric carcinogenesis is still poorly understood and, for this reason, preclinical research protocols were established that included the development of gastric cancer cell lines and the establishment of models of gastric carcinogenesis in non-human primates such as Sapajus apella. A comprehensive literature search was performed in relevant databases such as PubMed, ResearchGate, and Google Scholar to identify studies related to the topic. After an in-depth study of these reports, significant data were collected and compiled under appropriate headings. The main result of the studies carried out by the group on GC is the demonstration of the MYC gene overexpression as a common phenomenon in stomach carcinogenesis. Furthermore, we revealed that reducing the expression of the CDC25B gene, regulated by the MYC protein, is a therapeutic strategy against stomach tumors. This review article reveals preclinical evidence that treatment with menadione in experimental models of gastric tumorigenesis, in vivo and in vitro, inhibits the action of the phosphatase CDC25B and, consequently, prevents cell proliferation, invasion, and migration.

Menadione

Stomach cancer

10.2174/1871520622666220418131935

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Citations (3)

1514 In vivoCAR-M: redirecting endogenous myeloid cells with mRNA for cancer immunotherapy

Bindu Varghese Simone Mori Stefano Pierini Asen Bagashev Yumi Ohtani

Background

Pathologic response assessment after neoadjuvant treatment is the potential analog to radiographic response for advanced disease, with regard to study design, clinical care, and accelerated regulatory approvals. A standardized system for assessing degree of pathologic response in the primary tumor (PT) and lymph nodes (LNs) as a survival surrogate is an unmet need. It is also a prerequisite for determining whether patients with versus without LN involvement benefit from neoadjuvant therapy. Here, in a pre-specified exploratory analysis from CheckMate 816, we report the first in-depth assessment of the full spectrum of percent residual viable tumor (RVT; beyond pathologic complete response) in both the PT and LNs and its association with event-free survival (EFS). This study represents the first prospective use of such a pan-tumor scoring system in a phase 3 registrational trial.

Methods

Pathologic response was prospectively assessed in the randomized phase 3 study of neoadjuvant nivolumab plus chemotherapy versus chemotherapy alone in patients with resectable non-small cell lung carcinoma. Percentages of RVT, regression, and necrosis were quantified (0%-100%) in the PT and LNs using pan-tumor immune-related pathologic response criteria (irPRC). Pathologic features scored using this system were tested for association with EFS. An exploratory comparison between pathologic response, radiographic response, and circulating tumor DNA (ctDNA) clearance was performed.

Results

In both treatment arms and regardless of pathologic evidence of LN involvement, EFS was improved in patients with 0% versus >0% RVT-PT (HR=0.18). RVT-PT predicted EFS for nivolumab plus chemotherapy (AUC=0.74); 2-year EFS rates were 90%, 60%, 57%, and 39% for patients with 0%-5%, >5%-30%, >30%-80%, and >80% RVT, respectively. Each 1% increase in RVT associated with a 0.017 increase in HR for EFS. Combining pathologic response from PT+LNs helped differentiate outcomes. An increase in%necrosis was not observed in paired pre- and on-treatment specimens in either treatment arm. Further, necrosis within the on-treatment specimens was associated with lower EFS rates, arguing against necrosis as a histologic feature of treatment effect. When pathologic response was compared to radiographic response and ctDNA clearance, pathologic response best approximated EFS.

Conclusions

Percent RVT associates with improved EFS, supporting pathologic response as an emerging survival surrogate. Given the prognostic value of%RVT, its assessment using routine surgical pathology workflows, and a scoring system generalizable to any solid tumor type, it is also anticipated to become a biomarker for guiding subsequent adjuvant therapy. Further assessment of clinically-relevant%RVT cutoffs in PT+LN is warranted.

Acknowledgements

Funding for this study was provided by Bristol Myers Squibb and Ono Pharmaceutical Company Ltd.

Trial Registration

NCT02998528

Ethics Approval

This study was approved by the Johns Hopkins University Institutional Review Board.

Neoadjuvant Therapy

Surrogate endpoint

10.1136/jitc-2023-sitc2023.1514

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Citations (1)

Menadione reduces CDC25B expression and promotes tumor shrinkage in gastric cancer

Therapeutic Advances in Gastroenterology (2020)

Amanda Braga Bona Danielle Queiroz Calcagno Helem Ferreira Ribeiro José Augusto Pereira Carneiro Muniz Giovanny R. Pinto

Gastric cancer is one of the most incident types of cancer worldwide and presents high mortality rates and poor prognosis. MYC oncogene overexpression is a key event in gastric carcinogenesis and it is known that its protein positively regulates CDC25B expression which, in turn, plays an essential role in the cell division cycle progression. Menadione is a synthetic form of vitamin K that acts as a specific inhibitor of the CDC25 family of phosphatases.To better understand the menadione mechanism of action in gastric cancer, we evaluated its molecular and cellular effects in cell lines and in Sapajus apella, nonhuman primates from the new world which had gastric carcinogenesis induced by N-Methyl-N-nitrosourea. We tested CDC25B expression by western blot and RT-qPCR. In-vitro assays include proliferation, migration, invasion and flow cytometry to analyze cell cycle arrest. In in-vivo experiments, in addition to the expression analyses, we followed the preneoplastic lesions and the tumor progression by ultrasonography, endoscopy, biopsies, histopathology and immunohistochemistry.Our tests demonstrated menadione reducing CDC25B expression in vivo and in vitro. It was able to reduce migration, invasion and proliferation rates, and induce cell cycle arrest in gastric cancer cell lines. Moreover, our in-vivo experiments demonstrated menadione inhibiting tumor development and progression.We suggest this compound may be an important ally of chemotherapeutics in the treatment of gastric cancer. In addition, CDC25B has proven to be an effective target for investigation and development of new therapeutic strategies for this malignancy.

Menadione

10.1177/1756284819895435

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Citations (12)