Background:
Systemic therapy with conventional and targeted drugs is one of the principal modes of treatment of cancer, but the effectiveness of this therapy depends on the presence of respective molecular traits [1] and it is limited by drug resistance [2]. Drug resistance means that the treatment is effective initially in killing the cancer cells, but due to the heterogeneity of the cancer cells of the tumor and their ability to adapt to the treatment, some cancer cells become resistant to the drug given during the treatment [3]. This may result in the re-growth of the tumor although the patient is given the drug. Drug resistance remains one of the biggest challenges in cancer therapy, and it is important to obtain a better understanding of the molecular mechanisms underlying this process [2].
Aims of the project:
Two Master's projects are available:
The aim of the first Master's project is to elucidate the molecular mechanisms of targeted drugs used as anti-cancer treatments. Those drugs are substances used to precisely identify and attack certain types of cancer cells by blocking or inhibiting proteins that contribute in cancer progression. Many of the targeted agents are approved for a certain type of cancer and their activity might be affected by multiple molecular mechanisms both in terms of increasing and limiting drug activity. Different cancer types might have similar molecular alterations that can be exploited for a specific therapy. For example, drugs that are currently used to treat certain types of skin or ovarian cancer might be efficient against subtypes of colorectal cancer with similar molecular traits - also known as off-label use [4]. Furthermore, it is even possible to identify single patients that would benefit from targeted treatments with certain molecular characteristics. Therefore, the aim of this Master's project is to identify molecular mechanisms that explain the sensitivity or resistance to certain targeted drugs in primary models derived from patients with colorectal cancer. Also, the findings from this Master's project might contribute to personalized treatments for patients that participate in different clinical trials.
The objective of the second Master's project is to obtain a better understanding of the role of intercellular communication in drug resistance. One important type of intercellular communication occurs via specialized channels between neighboring cells, called gap junction channels. These channels allow for the direct transfer of ions and small molecules between adjacent cells [5]. Gap junction channels have numerous essential roles in human physiology, including the regulation of cell proliferation and differentiation and the maintenance of tissue homeostasis [5]. A large body of experimental work indicates that loss of intercellular communication via gap junction channels is involved in cancer pathogenesis [6]. Moreover, such loss can have a major impact on how cancer cells respond to chemotherapeutic drugs [6, 7]. This Master's project aims to increase our understanding of the molecular basis underlying the loss of gap junction channels during cancer pathogenesis, and how this contributes to resistance to chemotherapeutic drugs used in cancer treatment, with emphasis on cisplatin. Cisplatin is a platinum-based drug that is currently applied as first-line therapy for a number of cancer types, including testicular, cervical, ovarian, head, and neck cancer [8].
Methods:
Methods that will be used include monolayer and 3D cell culture, DNA/siRNA transfection, confocal microscopy, co-immunoprecipitation, Western blotting, live-cell imaging, assays for measuring cell viability, cell-cell communication assays, flow cytometry, gene expression analyses, and drug sensitivity screens.
Study and research environment:
The project will be carried out at The Department of Molecular Oncology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital. Our department currently has approximately 40 members, including several Master's and PhD students. We have a strong emphasis on teaching and supervising students, and members in our department are responsible for organizing the integrated MSc and PhD course BIOS5710/9710 Advanced Cancer Biology. The Master’s students starting on these two projects will work in close collaboration with other Master's and PhD students, as well as scientists, in the department. You can read more about our research department on this website: http://www.ous-research.no/molecularoncology/.
Supervisors:
- Edward Leithe (scientist, project group leader): Co-supervisor of the first Master's project and main supervisor of the second Master's project.
- Kushtrim Kryeziu (scientist; project group leader): Main supervisor of the first Master's project and co-supervisor of the second Master's project .
- Ragnhild A. Lothe (professor, department head): Internal supervisor of both Master's projects.
References:
- La Thangue NB, Kerr DJ: Predictive biomarkers: a paradigm shift towards personalized cancer medicine. Nat Rev Clin Oncol 2011, 8(10):587-596.
- Vasan N, Baselga J, Hyman DM: A view on drug resistance in cancer. Nature 2019, 575(7782):299-309.
- Cancer Drug Resistance: Unraveling Its Complexity; The National Cancer Institute.https://wwwcancergov/research/annual-plan/scientific-topics/drug-resistance.
- Green AK, Wood WA, Basch EM: Time to Reassess the Cancer Compendia for Off-label Drug Coverage in Oncology. JAMA 2016, 316(15):1541-1542.
- Goodenough DA, Paul DL: Gap junctions. Cold Spring Harb Perspect Biol 2009, 1(1):a002576.
- Aasen T, Leithe E, Graham SV, Kameritsch P, Mayan MD, Mesnil M, Pogoda K, Tabernero A: Connexins in cancer: bridging the gap to the clinic. Oncogene 2019, 38(23):4429-4451.
- Aasen T, Mesnil M, Naus CC, Lampe PD, Laird DW: Gap junctions and cancer: communicating for 50 years. Nat Rev Cancer 2016, 16(12):775-788.
- Rottenberg S, Disler C, Perego P: The rediscovery of platinum-based cancer therapy. Nat Rev Cancer 2021, 21(1):37-50.