A Novel Oncolytic Herpes Capable of Cell-Specific Transcriptional Targeting of CD133± Cancer Cells Induces Significant Tumor Regression

Inorganic nanoparticles hold great potential in the area of precision medicine, particularly for treating cancer owing to their unique physicochemical properties, biocompatibility and improved pharmacokinetics properties compared to their organic counterparts. Here we introduce strontium sulfite nanoparticles as new pH-responsive inorganic nanocarriers for efficient transport of siRNAs into breast cancer cells. We employed the simplest nanoprecipitation method to generate the strontium sulfite nanoparticles (SSNs) and demonstrated the dramatic roles of NaCl and d-glucose in particle growth stabilization in order to produce even smaller nanosize particles (Na-Glc-SSN) with high affinity towards negatively charged siRNA, enabling it to efficiently enter the cancer cells. Moreover, the nanoparticles were found to be degraded with a small drop in pH, suggesting their potential capability to undergo rapid dissolution at endosomal pH so as to release the payload. While these particles were found to be nontoxic to the cells, they showed higher potency in facilitating cancer cell death through intracellular delivery and release of oncogene-specific siRNAs targeting ros1 and egfr1 mRNA transcripts, than the strontium sulfite particles prepared in absence of NaCl and d-glucose, as confirmed by growth inhibition assay. The mouse plasma binding analysis by Q-TOF LC-MS/MS demonstrated less protein binding to smaller particles of Na-Glc-SSNs. The biodistribution studies of the particles after 4 h of treatment showed Na-Glc-SSNs had less off-target distribution than SSNs, and after 24 h, all siRNAs were cleared from all major organs except the tumors. ROS1 siRNA with its potential therapeutic role in treating 4T1-induced breast tumor was selected for subsequent in vivo tumor regression study, revealing that ROS1 siRNA-loaded SSNs exerted more significant anti-tumor effects than Na-Glc-SSNs carrying the same siRNA following intravenous administration, without any systemic toxicity. Thus, strontium sulfite emerged as a powerful siRNA delivery tool with potential applications in cancer gene therapy.

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Azurin, highly potent and selective anticancer agent for breast cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.13106 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 13106-13106

Author(s):

T. Yamada ◽

R. Mehta ◽

D. Majumdar ◽

A. M. Chakrabarty ◽

T. K. Das Gupta

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Tumor Volume ◽

Tumor Regression ◽

Treated Group ◽

Redox Protein ◽

The Mean ◽

The Difference ◽

Mcf 7

13106 Background: The use of live or attenuated pathogenic bacteria in the treatment of cancer dates back to the late nineteen hundreds when William B. Coley first reported that inducing Streptococcal infection resulted in tumor regression. However, the hazards of using live bacteria are obvious. Similarly, the results of using attenuated bacteria have been spotty and enthusiasm for it has waxed and waned. Recently, we have shown that redox protein azurin (14 kDa) secreted by an opportunistic pathogen, Pseudomonas aeruginosa, is not only cytotoxic to cancer cells in vitro but also produces tumor regression in athymic mice without producing any toxicity (PNAS, 99, 14098–14103, 2002; Science’s STKE, 158, tw416, 2002). Methods: In this study, we show the effect of 1mg/kg of azurin injected i.p. starting 72 hours after inoculation of 5x107 MCF-7 breast cancer cells in estradiol pretreated nude mice for 28 days (n = 20, control = 10, azurin-treated = 10). Results: Univariate analysis of the data showed the difference in tumor growth rates between control animals and azurin-treated animals was significant. For instance, 22 days after the start of treatment, the mean tumor volume in azurin-treated animals was only 22% of the mean tumor volume in the control mice (i.e., 0.0267 cm3 + 0.124 cm3 respectively, P = 0.0179 Kruskal-Wallis test). At the end of the experiment on the 29th day there was a reduction in the tumor volume by 85% in the treated group. We used a multivariate model, where the tumor growth over time was taken to be exponential with coefficients that were subject specific mixed effect (For control, tumor volumes = exp (−4.23 + 0.06 time) while for the treated group it was tumor volume = exp (−4.23 + 0.03 time)). The difference is statistically significant (P = 0.0456). Taken together, this in vivo data shows azurin exerts an inhibitory effect in the growth and progression of MCF-7 tumor xenotransplants. During the 28 days of treatment, treated animals did not show any sign of toxicity. Conclusions: Bacterial redox protein azurin can be explored as a novel therapeutic agent for treatment of breast cancer. Recently, we have prepared a truncated version of azurin which has 28 amino acids. It appers that this chemically synthesized peptide (2.8 kDa) has similar properties as azurin. No significant financial relationships to disclose.

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A Priori Activation of Apoptosis Pathways of Tumor (AAAPT) Technology: Development of Targeted Apoptosis Initiators for Cancer Treatment

10.1101/844605 ◽

2019 ◽

Author(s):

Raghu Pandurangi ◽

Marco Tomasetti ◽

Thillai Verapazham Sekar ◽

Ramasamy Paulmurugan ◽

Cynthia Ma ◽

...

Keyword(s):

Cell Death ◽

Cancer Cells ◽

Technology Development ◽

Tumor Regression ◽

A Priori ◽

Specific Cell ◽

Cell Death Pathways ◽

Survival Pathways ◽

Apoptosis Pathways

AbstractCancer cells develop tactics to circumvent the interventions by desensitizing themselves to interventions. The principle routes of desensitization include a) activation of survival pathways (e.g. NF-kB, PARP) and b) downregulation of cell death pathways (e.g. CD95/CD95L). As a result, it requires high therapeutic dose to achieve tumor regression which, in turn damages normal cells through the collateral damaging effects. Methods are needed to sensitize the low and non-responsive resistant tumor cells including cancer stem cells (CSCs) in order to evoke a better response from the current treatments. Current treatments including chemotherapy can induce cell death only in bulk cancer cells sparing CSCs and cancer resistant cells (CRCs) which are shown to be responsible for high recurrence of disease and low patient survival. Here, we report several novel tumor targeted sensitizers derived from the natural Vitamin E analogue (AMP-001-003). The drug design is based on a novel concept “A priori activation of apoptosis pathways of tumor technology (AAAPT) which is designed to activate specific cell death pathways and inhibit survival pathways simultaneously. Our results indicate that AMP-001-003 sensitize various types of cancer cells including MDA-MB-231 (triple negative breast cancer), PC3 (prostate cancer) and A543 (ling cancer) cells resulting in reducing the IC-50 of doxorubicin in vitro. At higher dose, AMP-001 acts as an anti-tumor agent on its own. The synergy between AMP-001 and doxorubicin could pave a new pathway to use AMP-001 as a neoadjuvant to chemotherapy to achieve a better efficacy and reduced off-target toxicity by the current treatments.Summary StatementA Priori Activation of Apoptosis Pathways of Tumor often referred to as “AAAPT” is a novel targeted tumor sensitizing technology which synergizes with chemotherapy to enhance the treatment efficacy.

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Suppression of poised oncogenes by ZMYND8 promotes chemo-sensitization

Cell Death and Disease ◽

10.1038/s41419-020-03129-x ◽

2020 ◽

Vol 11 (12) ◽

Author(s):

Shravanti Mukherjee ◽

Santanu Adhikary ◽

Shrikanth S. Gadad ◽

Payel Mondal ◽

Sabyasachi Sen ◽

...

Keyword(s):

Breast Cancer ◽

Drug Resistance ◽

Cancer Cells ◽

Tumor Regression ◽

Disease Free Survival ◽

Metastatic Breast ◽

Good Prognosis ◽

Sublethal Dose ◽

Tumorigenic Potential

AbstractThe major challenge in chemotherapy lies in the gain of therapeutic resistance properties of cancer cells. The relatively small fraction of chemo-resistant cancer cells outgrows and are responsible for tumor relapse, with acquired invasiveness and stemness. We demonstrate that zinc-finger MYND type-8 (ZMYND8), a putative chromatin reader, suppresses stemness, drug resistance, and tumor-promoting genes, which are hallmarks of cancer. Reinstating ZMYND8 suppresses chemotherapeutic drug doxorubicin-induced tumorigenic potential (at a sublethal dose) and drug resistance, thereby resetting the transcriptional program of cells to the epithelial state. The ability of ZMYND8 to chemo-sensitize doxorubicin-treated metastatic breast cancer cells by downregulating tumor-associated genes was further confirmed by transcriptome analysis. Interestingly, we observed that ZMYND8 overexpression in doxorubicin-treated cells stimulated those involved in a good prognosis in breast cancer. Consistently, sensitizing the cancer cells with ZMYND8 followed by doxorubicin treatment led to tumor regression in vivo and revert back the phenotypes associated with drug resistance and stemness. Intriguingly, ZMYND8 modulates the bivalent or poised oncogenes through its association with KDM5C and EZH2, thereby chemo-sensitizing the cells to chemotherapy for better disease-free survival. Collectively, our findings indicate that poised chromatin is instrumental for the acquisition of chemo-resistance by cancer cells and propose ZMYND8 as a suitable epigenetic tool that can re-sensitize the chemo-refractory breast carcinoma.

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Abstract LB115: Blocking p27Kip1phosphorylation with a liposomal:peptide drug induces Reactive Oxygen Species,necroptosis and tumor regression in breast cancer cells

10.1158/1538-7445.am2021-lb115 ◽

2021 ◽

Author(s):

Stacy Wister Blain ◽

Irina Jilishitz ◽

Jason L. Quinones ◽

Priyank Patel ◽

Grace Chen ◽

...

Keyword(s):

Breast Cancer ◽

Reactive Oxygen Species ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Tumor Regression ◽

Reactive Oxygen ◽

Oxygen Species

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Abstract 3405: PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition leads to tumor regression

10.1158/1538-7445.am2020-3405 ◽

2020 ◽

Author(s):

Joseph M. Gozgit ◽

Melissa M. Vasbinder ◽

Ryan P. Abo ◽

Kaiko Kunii ◽

Kristy G. Kuplast-Barr ◽

...

Keyword(s):

Cancer Cells ◽

Type I Interferon ◽

Tumor Regression ◽

Interferon Response ◽

Type I

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Intratumoral Injection of TLR4 Agonist (G100) Leads to Tumor Regression of A20 Lymphoma and Induces Abscopal Responses

Blood ◽

10.1182/blood.v126.23.820.820 ◽

2015 ◽

Vol 126 (23) ◽

pp. 820-820 ◽

Cited By ~ 5

Author(s):

Idit Sagiv-Barfi ◽

Hailing Lu ◽

Jessica Hewitt ◽

Frank J Hsu ◽

Jan ter Meulen ◽

...

Keyword(s):

T Cell ◽

Cancer Cells ◽

Research Funding ◽

Tumor Regression ◽

Cd8 T Cell ◽

Significant Loss ◽

Dependent Manner ◽

Th1 Cell ◽

Water Emulsion ◽

Tlr4 Agonist

Abstract Background: Toll-like receptors (TLRs) are components of the innate immune system that recognize pathogen-associated molecular patterns present on bacterial, fungal, or viral pathogens. Glucopyranosyl lipid A (GLA) is a synthetic TLR4 agonist that activates dendritic cells (DC) and enhances antigen-specific Th1 cell responses. Scientific question: Can an oil-in-water emulsion of GLA (G100) induce an anti-tumor effect due to modulation of the tumor microenvironment? Results: In our A20 murine lymphoma tumor model, intratumoral (i.t) administration of G100 resulted in tumor regression in approximately 50% of the mice in a dose dependent manner with an optimal dose of 10-20 μg/mouse. Surviving mice remained tumor-free at three months post G100 treatment and were resistant to a secondary tumor challenge with A20 cells, but not with CT26 colon cancer cells or 4T1 breast cancer cells. The effect was CD8+ T cell mediated as CD8+ depletion resulted in a significant loss of the effect. To examine the potential systemic effect of G100 i.t. treatment, Balb/c mice were implanted bilaterally with A20 tumors. Injection of G100 into the ipsilateral tumor three times a week resulted in an abscopal effect on the contralaterally implanted, untreated tumor, as evidenced by reduced tumor growth. Furthermore, the potential synergy between G100 and immunomodulatory antibodies was investigated: mice with bilateral A20 tumors received intratumoral G100 alone, systemic anti-PD-1 mAb alone, or a combination of both agents. Mice receiving combination therapy showed best overall survival, as measured by regression or reduced growth of both treated and untreated tumors. In addition, injection of low doses of anti-CTLA4 and anti-OX40 mAbs together with G100, directly into the tumor, was able to cure mice with established disease. Significance: Immunomodulatory antibodies are currently under clinical development for cancer treatment. We show here that combining these antibodies with a TLR4 agonist is sufficient to trigger a systemic anti-tumor response able to eradicate tumor at a distant site. This anti-tumor immune response was long lasting, specific and required CD8+ T cells as the effect was lost in CD8+ T cell depleted mice. Impact: We recently published positive results of intra-tumoral CpG (TLR9 agonist) in combination with immunomodulatory antibodies (Marabelle, Levy, et al. JCI, 2013). Both anti-CTLA4 and anti-PD1 antibodies have been FDA approved, and anti-PD-L1 and anti-OX40 antibodies are currently in advanced clinical trials. Our results suggest that G100 alone or in combination with immunomodulatory mAbs may be a promising new treatment for patients with injectable sites of lymphoma. Clinical studies investigating intratumoral G100 are underway. Disclosures Off Label Use: G100- a TLR4 agonist. Lu:Immune Design: Employment. Hewitt:Immune Design: Employment. Hsu:Immune Design: Employment. Meulen:Immune Design: Employment. Levy:Immune Design: Research Funding; Dynavax: Research Funding.

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Iron Oxide Nanoparticles as Carriers for DOX and Magnetic Hyperthermia after Intratumoral Application into Breast Cancer in Mice: Impact and Future Perspectives

Nanomaterials ◽

10.3390/nano10061016 ◽

2020 ◽

Vol 10 (6) ◽

pp. 1016 ◽

Cited By ~ 2

Author(s):

Susann Piehler ◽

Heidi Dähring ◽

Julia Grandke ◽

Julia Göring ◽

Pierre Couleaud ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Tumor Volume ◽

Tumor Regression ◽

Magnetic Hyperthermia ◽

Antitumor Effects ◽

Functionalized Magnetic Nanoparticles

There is still a need for improving the treatment of breast cancer with doxorubicin (DOX). In this paper, we functionalized magnetic nanoparticles (MNPs) with DOX and studied the DOX-induced antitumor effects in breast cancer cells (BT474) in the presence of magnetic hyperthermia (43 °C, 1 h). We show that i) intratumoral application of DOX-functionalized MNPs (at least at a concentration of 9.6 nmol DOX/100 mm3 tumor volume) combined with magnetic hyperthermia favors tumor regression in vivo, and there is evidence for an increased effect compared to magnetic hyperthermia alone or to the intratumoral application of free DOX and ii) the presence of the pseudopeptide NucAnt (N6L) on the MNP surface might well be beneficial in its function as carrier for MNP internalization into breast cancer cells in vitro, which could further augment the possibility of the induction of intracellular heating spots and cell death in the future.

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