Death rate in ovarian cancer has remained the same over the last 40 years because there has been little improvement in therapeutic strategies. A new study authored by a team or researchers at Cornell University and recently published in Cell offers a beacon of hope by showing that the immune system can be instructed to act as a first line of defense against ovarian cancer.
Ovarian cancer is a very heterogeneous disease that includes many molecular subtypes, driven by a number of different genetic alterations. It has long been known as a silent killer because symptoms usually manifest only at an advanced stage when treatment is rarely curative. For this reason much emphasis has been given to new ways of screening early ovarian cancer by trying to identify novel biomarkers or performing more frequent scans.
Surgery is the main treatment for most ovarian cancers. The extent of ovaries and uterus tissue removal depends on the stage of ovarian cancer at diagnosis. Standard first line treatment consists in combination therapy of a platinum compound, such as cisplatin or carboplatin, and a taxane, such as paclitaxel (Taxol®) or docetaxel (Taxotere®). Unfortunately ninety percent of patients have a recurrence, which indicates that tumors do not respond in a meaningful way to repeated rounds of chemotherapy and surgery, usually leading to more aggressive surgery, chemotherapy, radiotherapy, and surveillance.
Apart from some experimental studies, ovarian cancer is not treated with immunotherapy. Since immune-based approaches have succeeded in other lethal cancers, such as melanoma, scientists have started investigating whether engaging the immune system may be beneficial to ovarian cancer patients too.
A team of researchers at Cornell University has realized that ovarian cancer becomes a very hypoxic environment, in other words the tumor itself and the microenvironment around it are starved for oxygen because of the fast growing pace of cancer cells. To survive in such a hostile environment tumor cells upregulate the XBP1 gene that helps them detoxify and keep them active and capable of proliferating. In a study published on Cell researchers found that in preclinical models of ovarian cancer, tumor associated dendritic cells (DCs), a type of immune cells, similarly to cancer cells start expressing XBP1 following oxygen starvation. However, while this keeps DCs healthy it also inhibits their antitumor activity. DCs are antigen presenting cells that incorporate and expose on their surface fragments of tumor cells to activate another type of immune cells, called T cells that ultimately execute cancer cell death. When DCs expresses XBP1 they can no longer activate T cells to fight tumor growth.
How Can We Prevent Immune Cells Inactivation?
To rescue the immune cells ability to fight tumors the Cornell team injected tumor bearing mice with nanoparticles acting as a Trojan Horse: DCs intercept these circulating nanoparticles and respond by eating them up, much like they would do if they were pathogens. Once incorporated by DCs, the nanoparticles release their load, an inhibitor that silences XBP1 expression in the immune cells and renders them capable of activating T cells.
The team is now devising first-in-class drugs that can inhibit the activity of XBP1 in cancer cells and DC, which would both sensitize the cancer to treatment and restore an immune response against it.
Crown Bioscience has a longstanding interest in ovarian cancer research and is intrigued by the application of immunotherapy to novel types of cancer where its efficacy is currently being tested. Crown Bioscience has developed several highly predictive ovarian cancer models for preclinical drug evaluation included in our HuPrime® and PDXact™ collections of patients derived xenografts (PDX). Our immunotherapy resources include a range of platforms, with either murine or human immunity such as syngenic (bioluminescent and metastatic) models, GEMM, MuPrime™ (the murine version of HuPrime® ), HuMice™ (humanized mice produced through inoculating human hematopoietic cells into immunocompromised mice), and MiXeno™ (creating transient human immunity by mixing human peripheral blood mononucleated cells with xenograft models). We also support preclinical drug development through the use of our in vivo grade human and mouse isotype control antibodies.
Contact us today at busdev@crownbio.com to discuss how can we help driving forward your ovarian cancer research.
