INTRODUCING NOVEL COMBINATORIAL TARGETED THERAPIES IN MULTIPLE TYPES OF CANCER
The cancers of liver, colon and breast are amongst the top five most prevalent and most fatal worldwide. As the Raf/MEK/ERK pathway is frequently deregulated in hepatocellular carcinoma (HCC), sorafenib, a Raf kinase inhibitor, became the first systemic therapy approved for the treatment of patients...
Main Author: | |
---|---|
Format: | Others |
Published: |
VCU Scholars Compass
2016
|
Subjects: | |
Online Access: | http://scholarscompass.vcu.edu/etd/4088 http://scholarscompass.vcu.edu/cgi/viewcontent.cgi?article=5141&context=etd |
id |
ndltd-vcu.edu-oai-scholarscompass.vcu.edu-etd-5141 |
---|---|
record_format |
oai_dc |
spelling |
ndltd-vcu.edu-oai-scholarscompass.vcu.edu-etd-51412017-03-17T08:33:49Z INTRODUCING NOVEL COMBINATORIAL TARGETED THERAPIES IN MULTIPLE TYPES OF CANCER Tavallai, Mehrad The cancers of liver, colon and breast are amongst the top five most prevalent and most fatal worldwide. As the Raf/MEK/ERK pathway is frequently deregulated in hepatocellular carcinoma (HCC), sorafenib, a Raf kinase inhibitor, became the first systemic therapy approved for the treatment of patients with HCC. However, sorafenib only produced modest effects with low response rates in the clinic. Similarly, regorafenib, which was approved for the treatment of metastatic colorectal cancer (CRC), has had a poor response rate in the clinic. Since phosphodiesterase type 5 has been reported to be overexpressed in HCC and CRC, we hypothesized that sildenafil, a phosphodiesterase type 5 inhibitor, could enhance the toxicities of sorafenib and regorafenib in HCC and CRC cells, respectively. Our in vitro data indicated that the drugs interacted strongly to kill cancer cells via induction of ER stress, autophagy and apoptosis. In accordance with these findings, our in vivo data demonstrated a significant reduction in tumor growth. The second study in this manuscript was conducted based on the growing body of evidence about the significant contribution of EGFR and JAK/STAT signaling to the breast tumorigenesis. Our preliminary in vitro data demonstrated that the concurrent inhibition of these two pathways by lapatinib, a dual ERBB1/2 inhibitor, and ruxolitinib, a JAK1/2 inhibitor, synergistically killed breast cancer cells of all types, including the resistant triple negative subtype. Our mechanistic studies showed that the combination of ruxolitinib and lapatinib triggered cytotoxic mitophagy, and autophagy-dependent activation of BAX and BAK leading to the mitochondrial dysfunction. 2016-01-01T08:00:00Z text application/pdf http://scholarscompass.vcu.edu/etd/4088 http://scholarscompass.vcu.edu/cgi/viewcontent.cgi?article=5141&context=etd © The Author Theses and Dissertations VCU Scholars Compass Targeted Therapy Sorafenib Regorafenib PDE5 inhibitors Ruxolitinib Lapatinib Cancer Biology Translational Medical Research |
collection |
NDLTD |
format |
Others
|
sources |
NDLTD |
topic |
Targeted Therapy Sorafenib Regorafenib PDE5 inhibitors Ruxolitinib Lapatinib Cancer Biology Translational Medical Research |
spellingShingle |
Targeted Therapy Sorafenib Regorafenib PDE5 inhibitors Ruxolitinib Lapatinib Cancer Biology Translational Medical Research Tavallai, Mehrad INTRODUCING NOVEL COMBINATORIAL TARGETED THERAPIES IN MULTIPLE TYPES OF CANCER |
description |
The cancers of liver, colon and breast are amongst the top five most prevalent and most fatal worldwide. As the Raf/MEK/ERK pathway is frequently deregulated in hepatocellular carcinoma (HCC), sorafenib, a Raf kinase inhibitor, became the first systemic therapy approved for the treatment of patients with HCC. However, sorafenib only produced modest effects with low response rates in the clinic. Similarly, regorafenib, which was approved for the treatment of metastatic colorectal cancer (CRC), has had a poor response rate in the clinic. Since phosphodiesterase type 5 has been reported to be overexpressed in HCC and CRC, we hypothesized that sildenafil, a phosphodiesterase type 5 inhibitor, could enhance the toxicities of sorafenib and regorafenib in HCC and CRC cells, respectively. Our in vitro data indicated that the drugs interacted strongly to kill cancer cells via induction of ER stress, autophagy and apoptosis. In accordance with these findings, our in vivo data demonstrated a significant reduction in tumor growth.
The second study in this manuscript was conducted based on the growing body of evidence about the significant contribution of EGFR and JAK/STAT signaling to the breast tumorigenesis. Our preliminary in vitro data demonstrated that the concurrent inhibition of these two pathways by lapatinib, a dual ERBB1/2 inhibitor, and ruxolitinib, a JAK1/2 inhibitor, synergistically killed breast cancer cells of all types, including the resistant triple negative subtype. Our mechanistic studies showed that the combination of ruxolitinib and lapatinib triggered cytotoxic mitophagy, and autophagy-dependent activation of BAX and BAK leading to the mitochondrial dysfunction. |
author |
Tavallai, Mehrad |
author_facet |
Tavallai, Mehrad |
author_sort |
Tavallai, Mehrad |
title |
INTRODUCING NOVEL COMBINATORIAL TARGETED THERAPIES IN MULTIPLE TYPES OF CANCER |
title_short |
INTRODUCING NOVEL COMBINATORIAL TARGETED THERAPIES IN MULTIPLE TYPES OF CANCER |
title_full |
INTRODUCING NOVEL COMBINATORIAL TARGETED THERAPIES IN MULTIPLE TYPES OF CANCER |
title_fullStr |
INTRODUCING NOVEL COMBINATORIAL TARGETED THERAPIES IN MULTIPLE TYPES OF CANCER |
title_full_unstemmed |
INTRODUCING NOVEL COMBINATORIAL TARGETED THERAPIES IN MULTIPLE TYPES OF CANCER |
title_sort |
introducing novel combinatorial targeted therapies in multiple types of cancer |
publisher |
VCU Scholars Compass |
publishDate |
2016 |
url |
http://scholarscompass.vcu.edu/etd/4088 http://scholarscompass.vcu.edu/cgi/viewcontent.cgi?article=5141&context=etd |
work_keys_str_mv |
AT tavallaimehrad introducingnovelcombinatorialtargetedtherapiesinmultipletypesofcancer |
_version_ |
1718429354907664384 |