How Human Cytomegalovirus Infection Induces the Prolactin system in Ovarian Cancer

المشروع: Other project

تفاصيل المشروع

Description

There are still gaps in our knowledge of Prl and its role in tumor biology. New tools, suitable for Prl research range from transgenic animals, identification of pathways and different types of assays. Development of compounds blocking the Prl receptor is also significant. Such compounds can be used for human oriented investigations, which is relevant since the human Prl system differ in several ways from animal Prl systems. The idea in the present application is to further understand how Prl receptor antagonist work and internalized into the cells to open future doors for compounds of relevance for cancer to be conjugated to Prl and use the Prl receptor as mode of delivery into cancer cells with specific interest to ovarian cancer. We believe that this strategy accommodates the concept that future cancer treatments need to target several pathways. It is further one objective to investigate the possible significance of cancer stem cells in the relation to the Prl system. An important question is to resolve if increased levels of Prl receptors found in tumors de facto lead to an enhance uptake of drugs. Another line of investigation concerns how viral infection affects Prl signalling in the ovarian cancer. Surprising little is how viral particles interact with host gene/protein expression and our finding that CMV activate Prl signaling opens a new concept. Overall, the project is preclinical in nature but may open for future new treatment principles for ovarian cancer.

Layman's description

There are still gaps in our knowledge of Prl and its role in tumor biology. New tools, suitable for Prl research range from transgenic animals, identification of pathways and different types of assays. Development of compounds blocking the Prl receptor is also significant. Such compounds can be used for human oriented investigations, which is relevant since the human Prl system differ in several ways from animal Prl systems. The idea in the present application is to further understand how Prl receptor antagonist work and internalized into the cells to open future doors for compounds of relevance for cancer to be conjugated to Prl and use the Prl receptor as mode of delivery into cancer cells with specific interest to ovarian cancer. We believe that this strategy accommodates the concept that future cancer treatments need to target several pathways. It is further one objective to investigate the possible significance of cancer stem cells in the relation to the Prl system. An important question is to resolve if increased levels of Prl receptors found in tumors de facto lead to an enhance uptake of drugs. Another line of investigation concerns how viral infection affects Prl signalling in the ovarian cancer. Surprising little is how viral particles interact with host gene/protein expression and our finding that CMV activate Prl signaling opens a new concept. Overall, the project is preclinical in nature but may open for future new treatment principles for ovarian cancer.

Key findings

PROPOSED RESEARCH Background Prolactin (Prl) is a pituitary hormone with a well-established connection to infertility. For many years, Prl has been suspected to be a component of cancer (notably breast and prostate cancer) as well as certain autoimmune conditions (Systemic Lupus Erythematosus). Increased Prl secretion from the pituitary gland can be reduced by dopamine receptor agonists and although such treatment can cure infertility, clinical trials to reduce Prl secretion with dopamine receptor agonists has had no effect on cancer. More recently it was shown that human Prl is not only secreted from the pituitary gland but also by several extra pituitary tissues including cancer tissues. The concept that Prl seems to work as a paracrine growth factor led to research to block Prl effects at the receptor level instead of just reducing pituitary secretion. In a clinical trial, a Prl receptor blocking monoclonal antibody was used in advanced breast cancer - unfortunately without any effect. The Prl receptor is increased in different forms of cancer but genetic studies of the Prl receptor have not shown that this receptor is subject to activating mutations. In conclusion the Prl receptor is not be regarded an oncogene per se but may still be so called onco-modulatory. Viral infections have also been proposed to be onco-modulatory and this is the case with Cytomegalovirus (CMV). CMV is a virus that has infected most individuals and the virus can be re-activated from dormancy in cancer. The above stated leads to several questions yet to be answered. What is the role of Prl in cancer, is Prl of significance for cancer stem cells or for metastatic spread? What are the connections between Prl, infection and immunity? In previous work we have studied Prl in ovarian cancer (sbublished in biology 2020) and glioblastomas (published in oncotarget 2016, Alkharusi et al) - we found increased Prl receptor levels in these conditions and that Prl activates the STAT system leading to increased proliferation and cell survival. We have further developed an antagonist blocking the Prl receptor that has a proven effect in cultured cells. This receptor antagonist may find a future role in cancer treatment, but an emerging concept is that single target cancer treatment in many cases fail because tumor cells have ways to develop drug resistance - cancer is not only a simple defect in a single signaling pathway. In consideration of this we have started to chemically conjugate the Prl receptor antagonist with anti-cancer drugs with the idea to block several pathways in future studies. We have recently made a novel observation that experimental infection of cultured ovarian cancer cells with CMV increase local production of Prl and Prl receptor levels (results attached). This is an interesting observation and taken together with findings that CMV is frequently activated in ovarian cancer, one may suggest that one part of CMV activation include the activation of Prl as a local growth factor and that this of significance for cancer growth. In the present application we will further study the role of Prl in ovarian cancer. This form of cancer presents therapeutic challenges since surgery may not remove all cancer cells and the diagnosis is frequently late in tumor development. One of the potential biomarkers for ovarian cancer patients is high serum levels of Prl and can, in combination with other serum components e.g. CA125 predict ovarian cancer. The Prl receptor and HCMV proteins are frequently detected in ovarian tumor tissue specimen, but the mechanism behind it have so far not been investigated.
عنوان قصيرThere are still gaps in our knowledge of Prl and its role in tumor biology. New tools, suitable for Prl research range from transgenic animals, identification of pathways and different types of assays. Development of compounds blocking the Prl receptor is
اختصارTTotP
الحالةلم يبدأ

بصمة

استكشف موضوعات البحث التي تناولها هذا المشروع. يتم إنشاء هذه الملصقات بناءً على الجوائز/المنح الأساسية. فهما يشكلان معًا بصمة فريدة.