Our experiments indicate that the protective effects observed with CD47 blockade are mediated through upregulation of autophagic flux. However, the absence of CD47 in did not elicit a protective effect in cancer cells, but it enhanced macrophage-mediated cancer cell cytolysis. Therefore, the differential responses observed with CD47 blockade are due to autonomous activation of protective autophagy in normal tissue and enhancement immune cytotoxicity against cancer cells.
The high incidence of resistance to Tyrosine Kinase Inhibitors (TKIs) targeted against EGFR and downstream pathways has increased the necessity to identify agents that may be combined with these therapies to provide a sustained response for breast cancer patients. Here, we investigate the therapeutic potential of Ganoderma lucidum extract (GLE) in breast cancer, focusing on the regulation of the EGFR signaling cascade when treated with the EGFR TKI, Erlotinib. SUM-149, or intrinsic Erlotinib resistant MDA-MB-231 cells, and a successfully developed Erlotinib resistant cell line, rSUM-149 were treated with increasing concentrations of Erlotinib, GLE, or their combination (Erlotinib/GLE) for 72h. Treatment effects were tested on cell viability, cell proliferation, cell migration and invasion. To determine tumor progression, severe combined immunodeficient mice were injected with SUM-149 cells and then treated with Erlotinib/GLE or Erlotinib for 13 weeks. We assessed the protein expression of ERK1/2 and AKT in in vitro and in vivo models. Our results show that GLE synergizes with Erlotinib to sensitize SUM-149 cells to drug treatment, and overcomes intrinsic and developed Erlotinib resistance. Also, Erlotinib/GLE decreases SUM-149 cell viability, proliferation, migration and invasion. GLE increases Erlotinib sensitivity by inactivating AKT and ERK signaling pathways in our models. We conclude that a combinatorial therapeutic approach may be the best way to increase prognosis in breast cancer patients with EGFR overexpressing tumors.
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Inflammatory Breast Cancer (IBC) is the most lethal and rare form of breast cancer. It is characterized by rapid progression, local and distant metastases, younger age of onset, and lower overall survival compared with other breast cancers. Although IBC, like non-IBC breast cancers, is a heterogeneous disease and can occur as any of the five molecular breast cancer subtypes, they are most commonly either triple negative; or ER-, PR- and HER2+ overexpressed. There is no specific IBC treatment; thus, it seems feasible to find a therapeutic for this deadly disease. Our published data demonstrates that Ganoderma lucidum (Reishi) inhibits the viability of the triple negative IBC SUM149 cell line, but not of MCF10A noncancerous mammary epithelial cells. Consequently, in this study, we aimed to investigate Reishi effects in the viability of the ER-, PR-, HER2+ IBC cells lines SUM190 and KPL4. Also we studied the effects of Reishi on IBC cells when treated in complement with the HER2 Tyrosine Kinase Inhibitor, lapatinib (Tykerb®). Our hypothesis is that Reishi chemosensitizes IBC cells to lapatinib therapy. Herein, SUM190 and KPL-4 cells were treated with increasing concentrations of lapatinib and/or Reishi for 24 or 72h. Our results demonstrate that SUM190 and KPL-4 cells are sensitive to Reishi treatment. The combination of lapatinib plus Reishi reduced cell viability of SUM190 cells to 70% when treated with a concentration of 0.5mg/mL Reishi for 24h. Also, our data shows a reduction in cell viability of 94% in KPL-4 cells treated with lapatinib plus Reishi for 72h. We are currently directing our efforts to continue studying the contribution of Reishi in IBC cells when treated with lapatinib after 24 or 72h. Our results provide evidence that Reishi inhibits cancer cell viability and chemosensitizes IBC cells to lapatinib therapy, highlighting its anti-IBC-therapeutic potential. We thank Dr. Kurebayashi (Kawasaki Medical School, Japan) for providing KPL-4 cells. This project was sponsored by NIH/NCI #1F31CA174307 to ISA, Title V PPOHA US Department of Education #P031M105050 to UCC, NIH/RCMI #G12MD007583 to UCC, NIH/INBRE #5P20GM103475 to UPR/UCC and a research donation from the Commonwealth of Puerto Rico to UCC's University Center of Integral and Complementary Medicine (CUMIC)/MMM. Citation Format: Yismeilin Feliz-Mosquea, Ivette Suárez-Arroyo, Luis A. Cubano, Michelle M. Martínez-Montemayor. Synergistic effect between Ganoderma lucidum (Reishi) and lapatinib in HER2+ inflammatory breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3219. doi:10.1158/1538-7445.AM2014-3219
The development of immunotherapy is a major recent advance in clinical oncology. However the majority of patients do not respond and those who do, experience resistance and relapse. Therefore, understanding the molecular mechanisms of immune checkpoint inhibitor resistance is critical to develop combinatorial drug strategies to potentiate therapeutic responsiveness to reduce mortality. Highly secretory cells, such as T-cells, have a larger endoplasmic reticulum (ER) to handle the increased protein translation capacity required by the cell. Therefore, T-cells may be highly sensitive to ER stress. The high nutrient needs of the tumor deplete resources in the microenvironment subjugating infiltrating T-cells to reduced nutrient availability resulting in stress. Our data indicate that co-culturing melanoma cells with T-cells increase T-cell specific unfolded protein response (UPR) signaling. Stimulating ER stress decreased cytolytic T-cell function in TALL-104 T-cells, enabling Mun2b melanoma survival. Knockdown of PERK restored T-cell killing capacity in ER stress induced cells. In an ex-vivo model of antigen-specific mediated T-cell death, Pmel-1 T-cells stimulated with gp100 displayed increased B16 melanoma killing when treated with GSK2606414 (a small molecule PERK inhibitor). PERK inhibition also elevated glycolysis proteins and mitochondrial bioenergetics in T-cells, suggesting PERK inhibition increases T-cell metabolism. As proof-of-concept, we determined the effect of PERK inhibition in a syngeneic B16 melanoma model. Male C57/Bl6 mice were inoculated with B16 melanoma cells. At 5 days post injection, mice were treated with a control IgG, antisense morpholino targeting PERK, PD1 antibody, or a combination of PERK morpholino and PD1 antibody. PERK morpholino treatment alone was sufficient to reduce tumor volume by 46.5%. PD1 antibody therapy alone reduced tumor volume by 47.4%. The combination of PD1 antibody and PERK targeting therapy significantly reduced B16 melanoma tumor volume by 64.5% demonstrating that targeting PERK in vivo enhanced immunocheckpoint therapy efficacy. Treated B16 tumors were homogenized and infiltrating T-cells isolated by flow cytometry. Gated CD3+ infiltrating leukocytes were then counted for CD8 and PD1 expression. Tumor infiltrating CD8+ T-cells doubled with PERK inhibition alone, giving further proof indicating that PERK may be a novel immune checkpoint target. Small molecule PERK inhibitors were previously shown to cause β-islet damage and insulin resistance; therefore we tested the effect of our PERK morpholino on glucose tolerance in the B16 melanoma model. PERK morpholino treatment had no overall impact on glucose tolerance and therefore may be a novel therapeutic to induce T-cell metabolism and potentiate immune checkpoint therapy efficacy with reduced off-target toxicities. Citation Format: David R. Soto-Pantoja, Yismeilin R. Feliz-Mosquea, Kenysha YJ Clear, Adam S. Wilson, Katherine L. Cook. Targeting PKR-like endoplasmic reticulum kinase modulates metabolism to promote T-cell effector function and PD1 immunotherapy responsiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 449.
Inflammatory Breast Cancer (IBC) is an aggressive and unique form of breast cancer that develops rapidly. IBC, like non-IBC breast cancers, is a heterogeneous disease and can occur as any of the six molecular breast cancer subtypes. However, they are most commonly either triple negative; that is presenting with an absence of estrogen receptor (ER-), progesterone receptor (PR-) and the epidermal growth factor receptor 2 (HER2-) or ER-, PR- and HER2+ overexpressed. There is no specific IBC treatment; thus, it seems possible to find a therapeutic for this deadly disease. Our published data demonstrates that Ganoderma lucidum (Reishi) inhibits the viability of the triple negative IBC SUM149 cell line, but not of MCF10A noncancerous mammary epithelial cells. Subsequently, in this study, we aimed to investigate Reishi effects in the viability and molecular signaling of the ER-, PR-, HER2+ IBC cell lines SUM190, KPL-4 and IBC-3. Furthermore, we studied the effects of Reishi on IBC cells when treated in complement with the HER2 Tyrosine Kinase Inhibitor, lapatinib. The hypothesis for this study is that Reishi inhibits cancer cell viability and sensitizes IBC cells to lapatinib therapy and downregulates key proteins overexpressed in IBC. Herein, SUM190, KPL-4 and IBC-3 cells were treated with increasing concentrations of lapatinib and/or Reishi for 24 or 72h. The combination of lapatinib plus Reishi reduced cell viability of KPL-4 cells to 80% when treated with a concentration of 0.25 mg/mL of Reishi for 72h. Additionally, our data shows a reduction in cell viability of 70% in SUM190 cells treated with lapatinib plus Reishi for 72h. Also, Reishi and lapatinib downregulate the expression HER2 in KPL-4 cell after 72h of treatment. Our results provide evidence that Reishi inhibits cancer cell viability, highlighting the potential of Reishi as a natural anti-IBC-therapeutic. This project was sponsored by NIH/NCI #1F31 CA174307 to ISA, Title V PPOHA US Department of Education #P031M105050 to UCC/LAC, NIH/RCMI #G12 MD007583 to UCC/MMM, NIH/INBRE #5P20 GM103475 to UPR/UCC/MMM, NIH/NIMHD U54 MD008149 UH/MMM. Citation Format: Yismeilin Feliz-Mosquea, Ivette Suarez-Arroyo, Yaliz Loperena, Luis A. Cubano, Michelle M. Martinez-Montemayor. Enhancing response of Ganoderma lucidum (Reishi) and lapatinib in HER2+ inflammatory breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5556. doi:10.1158/1538-7445.AM2015-5556
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