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Dr Virna Leaner

Division of Medical Biochemistry, Faculty of Health Sciences, University of Cape Town

Title of the Project | Highlights of the Project | Peer-reviewed Publications | Value of Project in the Struggle against Cancer | Future Plans 

Title of the Project
The role of nuclear transport proteins in the development of cervical cancer Highlights of the Project

The major objective of this project was to characterise members of the nuclear transport proteins as both markers and potential therapeutic targets for cervical cancer. Our main findings are as follows:

• The nuclear transport proteins, Crm1, KpnB1 and KpnA2 are overexpressed in cervical cancer patient material and serve as promising cancer biomarkers.

• Crm1 and Kpn1 expression is required for the growth of cancer cells as inhibiting their expression blocks the proliferation and survival of cancer cells, suggesting that they are potential targets for therapeutic intervention.

Highlights of the project include:

• Acceptance of the study results for publication in the International Journal of Cancer

• Presentation of the study at both international and local conferences; V.Leaner (PI) presented aspects of this project at the American Association for Cancer Researchers (AACR) conferences (April 2006, November 2007, and April 2009) and at the African Organisation for Research and Training in Cancer (AORTIC) 2007 conference (Cape Town).
  

• Presentation of this research project at the CANSA Research in Action conference (Johannesburg) 20 August 2008.

• Pauline van der Watt (PhD student) received a prestigious award to present her research on this project at the FEBS/IUBMB Young Scientist Forum and 33rd FEBS Congress in Greece, June 2008 and at the South African Society for Biochemists and Molecular Biologist (SASBMB) Grahamstown, South Africa, January, 2008.

• Setting up a collaborative effort between researchers in different departments at UCT including; Medical Biochemistry, Anatomical Pathology and Obstetrics and Gynaecology and researchers at the National Institutes of Health, USA.

• The PI received two developing scientist awards for work done on this project and other cancer related projects; the NSTF/ NRF TW Kambule Award (2008) and the UCT Fellows Award (2007).

Peer-reviewed Publications Pauline J. van der Watt, Christopher P. Maske, Denver T. Hendricks, M. Iqbal Parker, Lynette Denny, Dhirendra Govender, Michael J. Birrer, and Virna D. Leaner., The Karyopherin proteins, Crm1 and Karyopherin Crm1, are overexpressed in cervical cancer and critical for cancer cell survival and proliferation. International Journal of Cancer. Apr 15;124(8):1829-40 (2009).. Click here to read the publication.

Peer-reviewed published conference proceedings:
Pauline J. van der Watt, Christopher P. Maske, Denver T. Hendricks, M. Iqbal Parker, Lynette Denny, Dhirendra Govender, Michael J. Birrer, and Virna D. Leaner. A critical role for the karyopherin proteins, Crm1 and Kpn beta 1, in cancer cell survival and proliferation. FEBS JOURNAL Volume: 275   Pages: 468-468   Supplement: Suppl. 1   JUN 2008.

Pauline van der Watt, Christopher Maske, Denver Hendricks, M. Iqbal Parker, Lynette Denny, Dhirendra Govender, Michelle Birrer and Virna Leaner. The Karyopherin proteins Crm1 and Kpnβ1 are overexpressed and critical for the survival of cervical cancer cells., American Association for Cancer Research Annual Meeting, Denver, Colorado, USA, 18-22 April 2009.

Pauline van der Watt, Christopher Maske, Denver Hendricks, M. Iqbal Parker, Lynette Denny, Dhirendra Govender, Michelle Birrer and Virna Leaner., Crm1 overexpression associates with cervical cancer and is critical for cell survival and proliferation. American Association for Cancer Research Centennial Meeting, Suntec, Singapore, 4-8 November 2007.

Pauline Forrester, Michael Birrer, Lynette Denny, Denver Hendricks, M. Iqbal Parker, and Virna Leaner, Transcriptional profiling identifies increased expression of nuclear transport proteins in cervical cancer. 97th American Association for Cancer Research Annual Meeting, Washington DC, USA., 1-5 April 2006. How was this Project of value in the Struggle against Cancer?
The struggle against cancer is compounded by the fact that it is such a complex disease that progresses through a series of stages before the development of an advanced stage cancer which is often exceeding difficult to treat. Research into understanding cancer development and treatment has therefore largely focused on:

1. the prevention of its occurrence
2. the early detection of disease
3. on identifying the most effective treatment strategies for patients who have the disease

The objective of our study has been to identify potential biomarkers for early detection as well identifying potential therapeutic targets.  We obtained preliminary data using cervical cancer tissue specimens that suggested that proteins in the nuclear transport family (the karyopherins; Crm1, KpnA2 and KpnB1), may serve as both biomarkers and therapeutic targets. We tested our hypothesis that these proteins could be essential for the biology of cancer cells by using cell culture model systems. The main findings emanating from our research, suggest the all three of the proteins could serve as potential biomarkers as their expression levels were significantly elevated in the cancer group compared to controls.

Our results however, suggest that only two of the three proteins investigated, Crm1 and KpnB1 are potential therapeutic targets as inhibiting their expression and activity in a variety of cancer cell lines including; cervical, oesophageal and breast cancer resulted in a significant inhibition in the growth of these cancer cells. It is our belief that continued research into the potential of these proteins as anti-cancer targets may ultimately result in the identification of small molecules that could be used to inhibit their expression and activity and in this way interfere with the uncontrolled growth of cancer cells.

Future Plans with the Project

This project has yielded promising data that we are in the process of investigating further. Some of the questions we are asking include:

1. can we identify small molecule inhibitors of the nuclear transport proteins (in particular KpnB1, as there is no known inhibitor to this protein identified to date)?
2. should we identify a small molecule inhibitor how effective is it at inhibiting cancer cell growth as opposed to normal cells?
3. why do these proteins become overexpressed in cancer cells (is it part cause or effect)?
4. what are the mechanism that control its gene expression?

We thank CANSA for their support in funding our research and for providing a forum (the CANCER in Action conference) for Cancer Researchers in South Africa to interact on a national level.