Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
  • American Association for Cancer Research (AACR)  (11)
  • 2020-2024  (11)
Type of Medium
Publisher
  • American Association for Cancer Research (AACR)  (11)
Language
Years
  • 2020-2024  (11)
Year
Subjects(RVK)
  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5733-5733
    Abstract: The impact of tumor matrix remodeling to the generation of an “inflamed” microenvironment that modulates responses to immunotherapy is unclear. Versican (VCAN) is a chondroitin sulphate matrix proteoglycan that promotes tolerogenic polarization of intratumoral DC through Toll-like receptor 2 (TLR2). Proteolytic processing of VCAN releases a bioactive N-terminal fragment (matrikine), versikine. In contrast to the tolerogenic actions of parental VCAN, versikine triggers IRF8-dependent transcription in myeloid cells and promotes Batf3-dendritic cell (DC) generation from FLT3L-mobilized bone marrow progenitors in vitro. Consistent with the Batf3-promoting effects of versikine, VCAN proteolysis correlates with T-cell infiltration across multiple cancers.The aims were to 1. define the impact of versikine on the intratumoral myeloid repertoire in vivo and 2. to define the efficacy of versikine as a vaccine adjuvant.4T1 breast carcinoma and Lewis Lung Carcinoma (LLC) empty vector (EV)- and versikine-expressing cells were implanted subcutaneously in syngeneic recipients. 1000mm3 tumors were harvested and intratumoral DC subsets were enumerated. Versikine-expressing tumors were characterized by significantly enhanced Batf3-DC (CD11chigh,MHC IIhigh Ly6C-, CD64-, CD24high,CD11blow) (p =0.0079 for 4T1 model and & lt;0.0001 for LLC model), whereas cDC2 (CD11chigh,MHC IIhigh Ly6C-, CD64-, CD24low, CD11bhigh ) frequency was diminished (p= 0.0079 and & lt;0.0001 respectively). Monocytic-derived DC (Mo-DC: CD11chigh, MHC IIhigh, Ly6C+, CD64+) remained unchanged. To determine the impact of versikine on responses to in situ vaccination using STING agonists, EV- and versikine-replete tumors (B16 and 4T1; 150 mm3), were injected intratumorally (IT) with a single subtherapeutic dose (200 μg) of DMXAA (murine STING agonist) or vehicle. EV-tumors did not significantly respond to 200μg DMXAA, whereas many B16-versikine and 4T1-versikine tumors regressed or growth was inhibited (p & lt;0.001 and p=0.014 respectively). Necrosis was frequently observed in 4T1 versikine-secreting tumors (6/9 mice) within 24 hours after treatment. Versikine extended survival after subtherapeutic DMXAA treatment in 4T1; log rank=p=0.01. Versikine's effects were abrogated in Batf3-null mice. To quantitate antigen-specific responses in the presence or absence of versikine, EV- and versikine-replete LLC tumors were injected IT with 500 μg DMXAA (therapeutic dose) or vehicle. We observed a significant increase in the frequency of CD8+ MHCI:SIINFEKL tetramer+ splenocytes in LLC-versikine-bearing animals as well as a marked increase in central memory T splenocytes (TCM) (CD62LhighCD44high). VCAN matrikines may generate effective adjuvants for in situ vaccination strategies across diverse solid and hematopoietic tumor types. Citation Format: Athanasios Papadas, Evan Flietner, Zachary Morrow, Joshua Wiesner, Alexander Cicala, Adam Pagenkopf, Chelsea Hope, Philip Emmerich, Dustin Deming, Jing Zhang, Peiman Hematti, Natalie Callander, Alexander Rakhmilevich, Mario Otto, Christian Capitini, Fotis Asimakopoulos. Versican proteolytic fragments (matrikines) synergize with STING agonists to elicit robust anti-tumor CD8+ T cell responses [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5733.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1521-1521
    Abstract: The development of effective adoptive T cell therapies to treat cancer patients has two main challenges. The first is identifying an antigen that is highly expressed in tumors with limited or no expression in normal tissues. The second is to develop a receptor that specifically binds to this antigen inducing potent anti-tumor activity without cross-reactivity to healthy cells. An additional challenge in the treatment of solid tumors is the hostile tumor microenvironment (TME) including the T cell inhibitory PD-1/PD-L1 axis. The cancer/testis antigen PRAME is an attractive target for immunotherapies of solid tumors using TCR-modified T cells as it is highly expressed in several solid tumor indications while its expression in normal tissues is mainly restricted to the testis. TCR candidates with high specificity for a PRAME-derived peptide presented on HLA-A2 were isolated from a non-tolerized T cell repertoire using our well-established high-throughput TCR generation process. Based on multi-parameter screening a lead TCR candidate was selected from more than 30 analyzed specific TCRs. T cells genetically modified to express the lead TCR (MDG1014) were characterized using a dedicated set of multi-parameter in vitro assays to evaluate specificity and activity. Favorable preclinical specificity was confirmed by analysis of the potential cross-recognition of partially homologous peptides presented on HLA-A2 and the allo-cross-recognition of common HLAs. In addition, no off-target toxicity was observed when testing a set of normal cells. Specific effector functions were confirmed by cytotoxicity and cytokine release assays using a panel of PRAME-positive tumor cell lines from various solid tumor types. Furthermore, the efficacy of MDG1014 was corroborated in a xenograft melanoma mouse model. To prevent the inhibition of T cells via the PD1-PD-L1 axis in the TME, we developed a switch receptor fusing the extracellular domain of PD1 with the intracellular signaling domain of 4-1BB. Co-expressing the switch receptor on MDG1014 in vitro led to enhanced proliferation and increased effector function against PRAME/PD-L1-positive tumor cell lines, including after repeated exposure, suggesting increased T cell fitness under chronic antigen stimulation. To confirm this effect in vivo, we have established a xenograft mouse model with tumor cells expressing PRAME and high PD-L1 levels, mimicking the TME of hard to treat solid tumors. In summary, we developed a TCR specific for an HLA-A2-restricted PRAME-epitope with high natural anti-tumor reactivity and specificity. Its favorable preclinical profile qualifies the TCR for evaluation in clinical trials. Combining this potent TCR with our PD1-41BB switch receptor results in a very promising T cell product, especially for the treatment of solid tumors. Citation Format: Ina Fetzer, Nadja Sailer, Melanie Salvermoser, Manon Weis, Christian Krendl, Maja Bürdek, Doris Brechtefeld, Isabella Rampp, Julian Rydzek-Wiesner, Monika Braun, Christian Ellinger, Christiane Geiger, Daniel Sommermeyer, Susanne Wilde. Combining a PRAME-specific TCR showing potent in vitro and in vivo anti-tumor reactivity and a favorable preclinical safety profile with a PD1-41BB switch receptor results in highly efficient T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1521.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 3
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 29, No. 6_Supplement_2 ( 2020-06-01), p. B058-B058
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 29, No. 6_Supplement_2 ( 2020-06-01), p. B058-B058
    Abstract: Introduction: Only 4% of the submissions to CLINVAR are from Latin American countries, similarly to Latino/Hispanic representation in other population genetic databases. We don’t know the spectrum of mutations affecting Colombian families with hereditary cancer syndromes; moreover, these cases are under diagnosed in our Country. We aimed to identify germline risk mutations in patients with a suspected hereditary cancer syndrome who were referred for genetic counseling at the largest cancer reference Institution in Colombia (INC-E.S.E.). Materials and methods: Descriptive cohort of patients referred to genetic counseling within the Hereditary Cancer Program at the INC-E.S.E. Germline genetic studies were performed on 147 individuals through NGS multi-gene panels and confirmed with Sanger sequencing or MLPA. Genetic results from more patients will be added to these statistics as those are being analyzed. Results: So far, results were obtained from 90 patients with a foreign company to study 83 genes, and 57 additional patients were studied at the INC-E.S.E., with a panel of 105 genes from Illumina in a MiSeq. Two bioinformatic pipelines (Illumina Variant Interpreter and SOPHIA Genetics) were used. Single Nucleotide Variants (SNVs), small insertions and deletions (INDELs), and Copy Number Variants (CNVs), were classified according to the ACMG criteria. Likely pathogenic or pathogenic mutations were identified in 22% of the patients (32/147). Of the total number of patients with an identified hereditary breast cancer syndrome (11/147, 7.48%), 6 are carriers of homologous repair genes mutation (3 in BRCA1, 1 in PALB2, 1 in CHEK2 and 1 in RAD51D); in BRCA1, one corresponds to the Colombian founder mutation A1708E and two carry the mutation BRCA1: c.1674delA (p.Gly559Valfs). The second most frequent was Lynch syndrome (8/147, 5.44%), 4 carry mutations in MLH1, 2 in PMS2, 1 in MSH6 and 1 in MSH2. It is interesting that 3/4 patients with mutations in MLH1 had the same splicing alteration (MLH1 c.790 + 1G & gt; A). Other 5 patients with a hereditary cancer syndrome were identified, including one of each: Li-Fraumeni, Multiple Endocrine Neoplasia type 1, Von Hippel Lindau, Neurofibromatosis 1 and MUTYH - Associated Polyposis (carrier of the two most frequent mutations in MUTYH; c.1187G & gt;A & c.536A & gt;G). Variants of Uncertain Significance (VUSs) were found in 47.62% and negative results in 32.65%. Conclusions: The finding of pathogenic mutations in 22% of this cohort is similar to what was previously reported for Colombia, but the percentage of VUSs is higher than other reports. Our lack of knowledge of the mutational spectrum in Colombians and our use of extensive multigene panels can explain this VUSs high rate. Citation Format: María Carolina Sanabria-Salas, Gonzalo Guevara, Ana Lucía Rivera, Antonio Huertas, Vilma Medina, Lina María Trujillo, Esperanza Peña, Carolina Wiesner. Germline mutation spectrum in hereditary cancer syndromes in a Latin American population [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B058.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036781-8
    detail.hit.zdb_id: 1153420-5
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 4
    In: Cancer Prevention Research, American Association for Cancer Research (AACR), Vol. 15, No. 1 ( 2022-01-01), p. 55-66
    Abstract: In Colombia, the human papillomavirus (HPV) vaccine was launched in 2012 in the context of a school-based national vaccination program targeting girls ages 9 to 14 and offering catch-up vaccination for girls ages 14 to 17. In this study, we evaluated the program's impact on type-specific HPV infection by comparing HPV cervical prevalence among vaccinated and nonvaccinated women. This is a comparative cross-sectional study conducted 5 years after the quadrivalent HPV vaccination implementation in a sentinel Colombian City. This study included young women (18–25 years old) who had been vaccinated in the catch-up group and were attending universities and technical institutions, and women who attended primary health care facilities for Pap smear screening. The HPV prevalence of 1,287 unvaccinated women was compared with the prevalence of 1,986 vaccinated women. The prevalence of HPV16/18 infections was significantly lower in vaccinated compared with unvaccinated women (6.5% vs. 15.4%; P & lt; 0.001), whereas for HPV6/11 infections, a decrease of 63.7% in vaccinated women (1.02% vs. 2.81%) was observed. The adjusted effectiveness to HPV16/18 was 61.4%; 95% CI, 54.3%–67.6%. However, the effectiveness against HPV16/18 was significantly higher among women vaccinated before their sexual debut 91.5%; 95% CI, 86.8–94.5, compared with effectiveness for vaccination after their sexual debut, 36.2%; 95% CI, 23.6–46.7. Five years after the introduction of HPV vaccines in Colombia, high effectiveness of HPV to prevent HPV16/18 infections is observed in the catch-up cohorts including virgin and sexually active women. Prevention Relevance: Monitoring HPV vaccines post-licensure plays an important role in assessing the progress of immunization programs, demonstrating the impact of vaccines on the population, and providing data for policy needs. In Colombia, HPV vaccines showed effectiveness when administered before start of sexual activity, and two doses are sufficient to achieve good protection.
    Type of Medium: Online Resource
    ISSN: 1940-6207 , 1940-6215
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2422346-3
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 5
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 13, No. 1 ( 2023-01-09), p. 70-84
    Abstract: The skin is exposed to viral pathogens, but whether they contribute to the oncogenesis of skin cancers has not been systematically explored. Here we investigated 19 skin tumor types by analyzing off-target reads from commonly available next-generation sequencing data for viral pathogens. We identified human papillomavirus 42 (HPV42) in 96% (n = 45/47) of digital papillary adenocarcinoma (DPA), an aggressive cancer occurring on the fingers and toes. We show that HPV42, so far considered a nononcogenic, “low-risk” HPV, recapitulates the molecular hallmarks of oncogenic, “high-risk” HPVs. Using machine learning, we find that HPV-driven transformation elicits a germ cell–like transcriptional program conserved throughout all HPV-driven cancers (DPA, cervical carcinoma, and head and neck cancer). We further show that this germ cell–like transcriptional program, even when reduced to the top two genes (CDKN2A and SYCP2), serves as a fingerprint of oncogenic HPVs with implications for early detection, diagnosis, and therapy of all HPV-driven cancers. Significance: We identify HPV42 as a uniform driver of DPA and add a new member to the short list of tumorigenic viruses in humans. We discover that all oncogenic HPVs evoke a germ cell–like transcriptional program with important implications for detecting, diagnosing, and treating all HPV-driven cancers. See related commentary by Starrett et al., p. 17. This article is highlighted in the In This Issue feature, p. 1
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2607892-2
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 6
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 29, No. 6_Supplement_1 ( 2020-06-01), p. A049-A049
    Abstract: Cancer is the second cause of mortality due to noncommunicable diseases in Colombia. In 2015 incident cases of breast (BC), gastric (GC), colorectal (CRC), and ovarian cancer (OC) attended at the Colombian National Cancer Institute (NCI) were 685, 498, 470, and 127, respectively. Although hereditary cancer syndromes are the minority of all cancer cases, the precise identification of individuals and relatives at high risk is a key aspect to the implementation of surveillance/screening, chemoprevention, and preventive surgery strategies for affected and unaffected carriers. In our country there are few studies conducted on hereditary cancer, and little is known about the spectrum of syndromes affecting Colombian families. In the Colombian NCI, we have designed and develop a comprehensive program for the registration, identification, diagnosis, management, and surveillance of cancer cases at high risk. Two main strategies where defined within this pilot program: 1) adjustment of the international protocols to the institutional context for identification and referral criteria of cancer patients with suspected syndrome to genetic counseling, genetic testing criteria, management, and surveillance, and 2) implementation of an institutional registry of patients with hereditary cancer, among other strategies. Also, first-degree relatives (FDR) of the affected carriers are offered to be tested and followed through the Center for Cancer Prevention and Early Detection (CPRED), recently established by the Colombian NCI. This Institutional ongoing program is providing genetic risk assessment to an average of 20 cancer patients per week since April 2018. The most frequent cancer we have attended is BC (56%), followed by CRC (10.5%), OC (6%), GC (5.5%), and others (22%). The average age at diagnosis was 47.3 for BC, 50.6 for CRC, 33.6 for OC, 39.4 for GC, and 47.8 years old (yo) for other cancers. Genetic testing has been offered to the patients according to the international guidelines. From all BC cases, the following fulfilled the Hereditary Breast and Ovarian Cancer (HBOC) criteria: i) 44.3% were diagnosed ≤ 45 yo, ii) 24% were diagnosed with triple-negative breast cancer (TNBC) at ≤ 60 yo, iii) 4% were TNBC cases diagnosed at & gt; 60 yo + ≥ 1 FDR/second-degree relative with BC at & lt; 50 yo, iv) 8% were patients with bilateral BC, v) 4% had a second primary tumor, and vi) 1.3% had Ashkenazi Jewish ancestry. From CRC cases, 50% were diagnosed at & lt; 50 yo regardless of family history of gastrointestinal cancers and 30% were diagnosed at ≥ 50 yo and fulfilled criteria for Lynch or Li Fraumeni syndromes. In the case of GC, 60% of the patients had diffuse gastric cancer subtype at & lt; 50 yo. Finally, all OC cases were submitted for genetic testing since all were diagnosed at & lt; 50 yo; 43% were tested for HBOC since they corresponded to papillary serous subtype and 29% fulfilled criteria for Peutz Jeghers syndrome. To our knowledge, this is the first genetic cancer risk assessment program in the country, based in the largest Colombian cancer hospital. Citation Format: María Carolina Sanabria-Salas, Gonzalo Guevara-Pardo, Antonio Huertas, Vilma Medina, Ana Lucía Rivera-Herrera, Juan Carlos Mejía, Jesús Acosta, Carolina Wiesner-Ceballo. Program for the identification, management and monitoring of patients and families at high risk of cancer in a Colombian National Cancer Reference Institution [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A049.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036781-8
    detail.hit.zdb_id: 1153420-5
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 7
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 21_Supplement ( 2020-11-01), p. PO-132-PO-132
    Abstract: The emergence of resistant cell clones to targeted therapies poses a significant issue in the treatment of metastatic melanoma. While these founding clones are often extremely rare in a starting population, their isolation and characterization holds unique potential for understanding disease processes, uncovering novel biomarkers and developing therapeutic concepts. The functional characterization of such founder clones and comprehensive comparisons to their post-selection counterparts requires live cells. To achieve this, we developed a novel lineage tracing tool termed CaTCH (CRISPRa tracing of clones in heterogeneous cell populations). CaTCH combines precise mapping of the lineage history of millions of cells with the ability to isolate any given clone alive from a complex population based on genetic barcodes. CaTCH thereby enables the retrospective isolation and analysis of founding clones from heterogeneous cell populations prior to evolutionary selection. In first applications, we use CaTCH to provide insights into the development of resistance to targeted cancer therapies. We demonstrate that CaTCH can be used to trace and isolate a single pre-existing therapy-resistant clone from a complex cancer cell population in vitro. Furthermore, we validate the utility of CaTCH for applications in vivo by investigating the origins of resistance to clinically relevant RAF/MEK inhibition in an immunocompetent melanoma mouse model. Here we find that most clones have the capacity to acquire resistance to combined RAF/MEK inhibitor therapy, indicating that resistance to this clinically relevant regimen is a universally achievable state in this model. We envision that CaTCH will address fundamental questions in basic and translational research (e.g., how cell identity states and trajectories are determined in therapy resistance, metastasis formation, tissue development and somatic cell re-programming), potentially revealing new vulnerabilities that can serve as targets for therapies. Citation Format: Christian Umkehrer, Felix Holstein, Laura Formenti, Julian Jude, Kimon Froussios, Tobias Neumann, Shona M. Cronin, Lisa Haas, Jesse Lipp, Thomas R. Burkard, Michaela Fellner, Thomas Wiesner, Johannes Zuber, Anna C. Obenauf. CaTCH - A barcode-guided CRISPRa-inducible reporter to isolate clones from heterogeneous populations [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-132.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 8
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 26, No. 20 ( 2020-10-15), p. 5424-5437
    Abstract: Small-molecule inhibitors have had a major impact on cancer care. While treatments have demonstrated clinically promising results, they suffer from dose-limiting toxicities and the emergence of refractory disease. Considerable efforts made to address these issues have more recently focused on strategies implementing particle-based probes that improve drug delivery and accumulation at target sites, while reducing off-target effects. Experimental Design: Ultrasmall ( & lt;8 nm) core-shell silica nanoparticles, C′ dots, were molecularly engineered to function as multivalent drug delivery vehicles for significantly improving key in vivo biological and therapeutic properties of a prototype epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib. Novel surface chemical components were used to conjugate gefitinib–dipeptide drug-linkers and deferoxamine (DFO) chelators for therapeutic delivery and PET imaging labels, respectively. Results: Gefitinib-bound C′ dots (DFO-Gef-C′ dots), synthesized using the gefitinib analogue, APdMG, at a range of drug-to-particle ratios (DPR; DPR = 11–56), demonstrated high stability for DPR values≤ 40, bulk renal clearance, and enhanced in vitro cytotoxicity relative to gefitinib (LD50 = 6.21 nmol/L vs. 3 μmol/L, respectively). In human non–small cell lung cancer mice, efficacious Gef-C′ dot doses were at least 200-fold lower than that needed for gefitinib (360 nmoles vs. 78 μmoles, respectively), noting fairly equivalent tumor growth inhibition and prolonged survival. Gef-C′ dot–treated tumors also exhibited low phosphorylated EFGR levels, with no appreciable wild-type EGFR target inhibition, unlike free drug. Conclusions: Results underscore the clinical potential of DFO-Gef-C′ dots to effectively manage disease and minimize off-target effects at a fraction of the native drug dose.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 9
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 26, No. 1 ( 2020-01-01), p. 147-158
    Abstract: Small-molecule inhibitors have revolutionized treatment of certain genomically defined solid cancers. Despite breakthroughs in treating systemic disease, central nervous system (CNS) metastatic progression is common, and advancements in treating CNS malignancies remain sparse. By improving drug penetration across a variably permeable blood–brain barrier and diffusion across intratumoral compartments, more uniform delivery and distribution can be achieved to enhance efficacy. Experimental Design: Ultrasmall fluorescent core-shell silica nanoparticles, Cornell prime dots (C' dots), were functionalized with αv integrin-binding (cRGD), or nontargeting (cRAD) peptides, and PET labels (124I, 89Zr) to investigate the utility of dual-modality cRGD-C' dots for enhancing accumulation, distribution, and retention (ADR) in a genetically engineered mouse model of glioblastoma (mGBM). mGBMs were systemically treated with 124I-cRGD- or 124I-cRAD-C' dots and sacrificed at 3 and 96 hours, with concurrent intravital injections of FITC-dextran for mapping blood–brain barrier breakdown and the nuclear stain Hoechst. We further assessed target inhibition and ADR following attachment of dasatinib, creating nanoparticle–drug conjugates (Das-NDCs). Imaging findings were confirmed with ex vivo autoradiography, fluorescence microscopy, and p-S6RP IHC. Results: Improvements in brain tumor delivery and penetration, as well as enhancement in the ADR, were observed following administration of integrin-targeted C' dots, as compared with a nontargeted control. Furthermore, attachment of the small-molecule inhibitor, dasatinib, led to its successful drug delivery throughout mGBM, demonstrated by downstream pathway inhibition. Conclusions: These results demonstrate that highly engineered C' dots are promising drug delivery vehicles capable of navigating the complex physiologic barriers observed in a clinically relevant brain tumor model.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 10
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 13 ( 2022-07-01), p. 2938-2952
    Abstract: Despite dramatic growth in the number of small-molecule drugs developed to treat solid tumors, durable therapeutic options to control primary central nervous system malignancies are relatively scarce. Chemotherapeutic agents that appear biologically potent in model systems have often been found to be marginally effective at best when given systemically in clinical trials. This work presents for the first time an ultrasmall ( & lt;8 nm) multimodal core-shell silica nanoparticle, Cornell prime dots (or C′ dots), for the efficacious treatment of high-grade gliomas. Experimental Design: This work presents first-in-kind renally clearable ultrasmall ( & lt;8 nm) multimodal C′ dots with surface-conjugated doxorubicin (DOX) via pH-sensitive linkers for the efficacious treatment in two different clinically relevant high-grade glioma models. Results: Optimal drug-per-particle ratios of as-developed nanoparticle–drug conjugates were established and used to obtain favorable pharmacokinetic profiles. The in vivo efficacy results showed significantly improved biological, therapeutic, and toxicological properties over the native drug after intravenous administration in platelet-derived growth factor–driven genetically engineered mouse model, and an EGF-expressing patient-derived xenograft (EGFR PDX) model. Conclusions: Ultrasmall C′ dot–drug conjugates showed great translational potential over DOX for improving the therapeutic outcome of patients with high-grade gliomas, even without a cancer-targeting moiety.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. Further information can be found on the KOBV privacy pages