Ola Larsson

Plasmodium falciparum is a parasite that causes human malaria which remains one of the most important infectious diseases worldwide. Managing this global emergency will require a deeper understanding of the resistance mechanisms developed by the parasite to survive in the presence of artemisnins,  as well as opening up new therapeutic avenues. As of recently, mounting evidence converges to suggest a strong tie between the phenotypic characteristics of artemisinin resistance to general cellular stress response mechanisms. In this project proposal, we suggest to conduct a comprehensive investigation on the systemicregulation of translation during stress responses in the parasite P. falciparum. We will approach this by first establishing a deeper understanding of the ribosome and the tRNA biology in the parasite with the use of various molecular assays and subsequently decipher how the regulation of  two abundant ncRNA classes may affect the translatome and the functional proteome output during stress conditions. Together with the preliminary data we have already obtained, this project aims to achieve the followings:1. To characterize a novel and universally conserved ribosome associated factor in P.falciparum and its role in stress responses.2. To provide supporting evidence for the presence of functionally specializedribosomes.3. To identify common stress response pathways through studying the tRNAepitranscriptome.4. To develop a high-throughput drug screening assay.

In spite of some exciting advances in the treatment of breast cancer, a diagnosis of metastasis still remains deadly in many. Existing therapies often fail in women with metastatic breast cancer, and oncologists sadly inform their patients that there are no further treatment options. We need a new way to block metastasis. Based on the data we have acquired, we propose that blocking faulty protein synthesis in cancer associated fibroblasts, using drugs that block MNK1/2, will inhibit metastasis. The goal of our research is to better understand the biology of MNK1/2 and how their activation promotes metastasis. The activity of MNK1/2 in cancer associated fibroblasts (CAF), which are metastasis promoting cells, remains unknown. We will clarify this using mouse models and breast tumors from women being treated with MNK1/2 inhibitors in our clinical trial. Ultimately, we seek to identify biomarkers to predict response to MNK1/2 inhibitors, which may include CAF-specific proteins. Our project brings together experts in oncology, translational control, proteomics, and MNK1/2 biology, all dedicated to the success of the proposed work. We will use in vitro/in vivo metastasis models. A unique advantage of our project is that we have access to tumors from women with metastatic breast cancer, who are being treated with MNK1/2 inhibitors in our clinical trial. The samples will be imaged to provide an unprecedented view of the impacts of MNK1/2 inhibition to the tumor landscape. Metastasis remains the leading cause of breast cancer related deaths. MNK1/2 inhibitors are currently in clinical trials for the treatment of cancer, including at our institution. Importantly, we propose that MNK1/2 inhibitors will be most effective for treating metastasis. If we are correct, we would be impacting not only the 20-30% of patients diagnosed with breast cancer who will develop metastasis, but also their families. We will work with the Quebec Breast Cancer Foundation (see letter) to communicate our research results to the public, as we have done in the past. Our project provides hope to women with metastatic breast cancer.

A majority of all women who die as a result of breast cancer belong to a category of breast cancer that expresses the estrogen receptor. This is because most breast cancer patients belong to that category and because resistance to treatment focuses on inhibition of the estrogen receptor, so-called endocrine therapy, continues to occur for at least 20 years after the cancer has been removed. There is currently a lack of effective treatments for breast cancer that have developed resistance to endocrine therapy and it is therefore of utmost importance to find molecular targets that can be used to treat these patients. When genes are expressed, a copy (mRNA) is first made which is used to produce proteins via so-called translation. The estrogen receptor is a key factor for which genes to copy. We have recently discovered that the estrogen receptor also affects which of these mRNAs are translated into proteins. Our preliminary data show that if the estrogen receptor can not affect the translation of mRNA into proteins, it can also not affect cell division, which is one of its key functions in cancer cells. It also seems that if you inhibit the translation that is regulated by the estrogen receptor, you can make cancer cells again sensitive to endocrine treatment. We want to clarify whether translation of mRNA can be used as a target for the treatment of breast cancer with resistance to endocrine therapy. We also want to study, using tissue samples from original breast tumors and their metastases, whether up-regulation of mRNA translation is associated with metastasis. Furthermore, by comparing patients with short and long time to recurrence, we will investigate whether misregulation of mRNA translation is associated with cancer recurrence. Through these studies, we will understand whether translation of mRNA is a target for the treatment of breast cancer that has developed resistance to endocrine therapy.