Ignite Creation Date:
2024-10-26 @ 3:34 PM
Last Modification Date:
2024-10-26 @ 3:34 PM
Study NCT ID:
NCT06502249
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-06-12
Brief Title:
Modulatory Effect of Prodigiosin or Pioglitazone on TIME and the Crosstalk to Immune-Checkpoint Proteins
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Modulatory Effect of Prodigiosin or Pioglitazone on Tumor Immune Microenvironment and the Crosstalk to Immune-Checkpoint Proteins
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Lung cancer is one of the most common and serious types of cancer Lung tumor cells exploit immune checkpoint proteins ICPs to maintain immune tolerance and thus promote tumor progression and invasion Inhibition of ICPs using antibody therapies is one of the most common approaches for the treatment of lung cancer Unfortunately these antibody-based therapies can lead to severe adverse events Moreover a significant number of patients do not respond to immune checkpoint inhibition due to tumor heterogeneity and the immunosuppressive tumor immune microenvironment TIME The use of small molecule targeted approach instead of antagonizing antibodies may have the potential advantage of being able to target multiple ICPs in TIME with a single agent as well as improved tumor distribution
Detailed Description:
1 Introduction 11 Background Components of the tumor microenvironment TME presented by immune cells tumor cells and their derived factors are known as Tumor immune microenvironment TIME Tumors can gradually shape TIME into an immunosuppressive state to hinder host immunity Two opposing immune responses help shape TIME One side of the immune cells represented by M1 macrophage T-lymphocyte Dendritic cells DC and Natural killer cells NK play a role in the antitumor immune response On the contrary tumor-promoting immune cells represented by regulatory T cells Treg myeloid-derived suppressor cells MDSC M2 macrophage and group 2 innate lymphoid cells ILC2 contribute to an immunosuppressive microenvironment
Under physiological conditions several immune checkpoint proteins ICPs are expressed on various immune cells These ICPs bind to their complementary ligand to activate T-cells inhibitory signals therefore they act as gatekeepers for normal cells Among the first immune checkpoint proteins discovered were cytotoxic T-lymphocyte antigen number 4 CTLA-4 and programmed cell death protein 1 PD-1 Recently several immune checkpoint proteins have been discovered T-cell immunoglobulin domain and mucin domain-containing molecule-3 TIM-3 T-cell immunoglobulin and ITIM domain TIGIT B and T cell lymphocyte attenuator BTLA lymphocyte activation gene LAG3 and V-domain Ig suppressor of T cell activation VISTA Unfortunately tumor and tumor-promoting immune cells exploit these ICPs to escape immune system-mediated cell death
Several factors could control the expression of ICPs HSP90 chaperone function plays a role in the regulation of immune cell function by controlling ICPs expression Zavareh and his colleagues showed that HSP90 inhibitors have a direct inhibitory effect on the expression of ICPs including PD-L1 and PD-L2 Only one study implicated prodigiosin inhibitory effect on HSP90 yet the effect of prodigiosin on novel immune checkpoint proteins and its modulatory effect on TIME via HSP90 has not been investigated
The expression of ICPs has also been shown to be controlled by the IL-6JAK2STAT3 pathway High levels of STAT3 and JAK2 levels have been attributed to poor prognosis in non-small cell lung cancer NSCLC patients c-MYC one of the downstream targets of IL-6STAT3 signaling could promote tumor immune escape by increasing the levels ICPs Pioglitazone a peroxisome proliferator-activated receptor-γ agonist inhibited c-MYC-mediated immune escape by inducing PD-L1 protein degradation Pioglitazone could enhance cancer immunotherapy and T-cell activation by decreasing PD-L1 protein levels The inhibitory effect of pioglitazone on STAT3 has been studied in different types of cancer However the modulatory effect of pioglitazone on novel ICPs via the IL-6STAT3 pathway and c-MYC remains to be investigated
12 PROBLEM 121Lung Cancer is the leading cause of cancer death in both men and women aged 50 years and older The response rate to current ICIs used for the treatment of lung cancer is far from satisfactory
122 Cancer cells escape from immune surveillance through immune-editing Further research is needed for a better understanding of different immune aspects of lung cancer including immune escape immunosuppression immune editing and tumor-intrinsic adaptive response
3 Proposal state of the art 31 TIME is a dynamic process and despite heterogeneity across different cancer types and populations the role of TIME in tumor progression is similar 32 The expression of ICPs could be regulated by HSP90 IL-6JAK2STAT3 Pathway and c-MYC Thus HSP90 inhibition by prodigiosin as well as IL-6STAT3 and c-MYC inhibition by pioglitazone could have the potential to enhance immune surveillance and immune checkpoint protein blockade therapy
4 Aim of the work 41 Measuring gene and protein expression of Heat shock Protein 90 HSP90 IL-6 STAT3 c-MYC and novel immune checkpoint proteins from non-small cell lung cancer NSCLC patients
42 Studying the effect of prodigiosin on HSP90and pioglitazone of IL-6STAT3 and c-MYC for modulating TIME via the expression of one of the novel immune checkpoint proteins
43 Investigate the difference in expression at both protein and mRNA levels following treatment of prodigiosin and pioglitazone on lung cancer cell lines A549 or H460 or Calu-3
44 Loading both drugs in nano-sized particles NPs and testing the efficacy against lung cancer cell model both in-vivo and in-vitro
5 Research objectives 51 Main objectives
Identifying and targeting promising molecular targets to help eradicate lung tumor cells and prevent the development of treatment resistance or immune resistance
52 Secondary objectives
521 Studying the cytotoxic effect of prodigiosin and pioglitazone on lung cancer cell line and in vitro safety assay towards normal human retina pigmented epithelial RPE1 cell line
522 Identification of cell surface markers expressed by various immune cells on lung cancer cell lines A549 or H460 or Calu-3 using flow cytometry
523 Cell treatment with prodigiosin and HSP90 transfection in lung cancer cell lines for further investigation of the modulatory effect of Prodigiosin on TIME
524 Cell treatment with pioglitazone and c-MYC transfection or using JAK2STAT3 inhibitor in lung cancer cell lines for further investigation of the modulatory effect of Pioglitazone on TIME
525 Gene expression and measuring protein levels of HSP90 and the novel immune checkpoint proteins before and after the addition of prodigiosin in lung cancer cell line
526 Gene expression and measuring protein levels of IL-6 STAT3 c-MYC and the novel immune checkpoint proteins before and after the addition of pioglitazone in lung cancer cell line
527 Studying the in-vivo and in-vitro effects of drug-load nanoparticles in lung cancer model
Under physiological conditions several immune checkpoint proteins ICPs are expressed on various immune cells These ICPs bind to their complementary ligand to activate T-cells inhibitory signals therefore they act as gatekeepers for normal cells Among the first immune checkpoint proteins discovered were cytotoxic T-lymphocyte antigen number 4 CTLA-4 and programmed cell death protein 1 PD-1 Recently several immune checkpoint proteins have been discovered T-cell immunoglobulin domain and mucin domain-containing molecule-3 TIM-3 T-cell immunoglobulin and ITIM domain TIGIT B and T cell lymphocyte attenuator BTLA lymphocyte activation gene LAG3 and V-domain Ig suppressor of T cell activation VISTA Unfortunately tumor and tumor-promoting immune cells exploit these ICPs to escape immune system-mediated cell death
Several factors could control the expression of ICPs HSP90 chaperone function plays a role in the regulation of immune cell function by controlling ICPs expression Zavareh and his colleagues showed that HSP90 inhibitors have a direct inhibitory effect on the expression of ICPs including PD-L1 and PD-L2 Only one study implicated prodigiosin inhibitory effect on HSP90 yet the effect of prodigiosin on novel immune checkpoint proteins and its modulatory effect on TIME via HSP90 has not been investigated
The expression of ICPs has also been shown to be controlled by the IL-6JAK2STAT3 pathway High levels of STAT3 and JAK2 levels have been attributed to poor prognosis in non-small cell lung cancer NSCLC patients c-MYC one of the downstream targets of IL-6STAT3 signaling could promote tumor immune escape by increasing the levels ICPs Pioglitazone a peroxisome proliferator-activated receptor-γ agonist inhibited c-MYC-mediated immune escape by inducing PD-L1 protein degradation Pioglitazone could enhance cancer immunotherapy and T-cell activation by decreasing PD-L1 protein levels The inhibitory effect of pioglitazone on STAT3 has been studied in different types of cancer However the modulatory effect of pioglitazone on novel ICPs via the IL-6STAT3 pathway and c-MYC remains to be investigated
12 PROBLEM 121Lung Cancer is the leading cause of cancer death in both men and women aged 50 years and older The response rate to current ICIs used for the treatment of lung cancer is far from satisfactory
122 Cancer cells escape from immune surveillance through immune-editing Further research is needed for a better understanding of different immune aspects of lung cancer including immune escape immunosuppression immune editing and tumor-intrinsic adaptive response
3 Proposal state of the art 31 TIME is a dynamic process and despite heterogeneity across different cancer types and populations the role of TIME in tumor progression is similar 32 The expression of ICPs could be regulated by HSP90 IL-6JAK2STAT3 Pathway and c-MYC Thus HSP90 inhibition by prodigiosin as well as IL-6STAT3 and c-MYC inhibition by pioglitazone could have the potential to enhance immune surveillance and immune checkpoint protein blockade therapy
4 Aim of the work 41 Measuring gene and protein expression of Heat shock Protein 90 HSP90 IL-6 STAT3 c-MYC and novel immune checkpoint proteins from non-small cell lung cancer NSCLC patients
42 Studying the effect of prodigiosin on HSP90and pioglitazone of IL-6STAT3 and c-MYC for modulating TIME via the expression of one of the novel immune checkpoint proteins
43 Investigate the difference in expression at both protein and mRNA levels following treatment of prodigiosin and pioglitazone on lung cancer cell lines A549 or H460 or Calu-3
44 Loading both drugs in nano-sized particles NPs and testing the efficacy against lung cancer cell model both in-vivo and in-vitro
5 Research objectives 51 Main objectives
Identifying and targeting promising molecular targets to help eradicate lung tumor cells and prevent the development of treatment resistance or immune resistance
52 Secondary objectives
521 Studying the cytotoxic effect of prodigiosin and pioglitazone on lung cancer cell line and in vitro safety assay towards normal human retina pigmented epithelial RPE1 cell line
522 Identification of cell surface markers expressed by various immune cells on lung cancer cell lines A549 or H460 or Calu-3 using flow cytometry
523 Cell treatment with prodigiosin and HSP90 transfection in lung cancer cell lines for further investigation of the modulatory effect of Prodigiosin on TIME
524 Cell treatment with pioglitazone and c-MYC transfection or using JAK2STAT3 inhibitor in lung cancer cell lines for further investigation of the modulatory effect of Pioglitazone on TIME
525 Gene expression and measuring protein levels of HSP90 and the novel immune checkpoint proteins before and after the addition of prodigiosin in lung cancer cell line
526 Gene expression and measuring protein levels of IL-6 STAT3 c-MYC and the novel immune checkpoint proteins before and after the addition of pioglitazone in lung cancer cell line
527 Studying the in-vivo and in-vitro effects of drug-load nanoparticles in lung cancer model
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None