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California State University, Bakersfield

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When cancer metastasizes, or spreads to a new part of the body, the patient’s prognosis often becomes fatal. An enzyme known as lysyl oxidase (LOX) is believed to play a critical role in cancer metastasis. Higher levels of the LOX enzyme are associated with increased fatalities of metastatic cancer patients.1 In breast cancer cells, reducing LOX decreased and, in some cases, even eliminated metastasis.2 Thus metastatic tumors can be treated, or even prevented if we can develop a method for reducing the activity of LOX. The goal of this project is to design and prepare molecules that sabotage the LOX enzyme, ideally leading to the development of a drug that can prevent cancer metastasis. Our strategy utilizes β-aminopropionitrile (BAPN), a known LOX inhibitor, to achieve this objective.3 We will design and prepare several molecules that have the capability of selectively delivering BAPN to tumor cells.
Research has demonstrated that BAPN treatment significantly reduces the frequency of breast cancer metastasis.4 Unfortunately, BAPN cannot be used as a drug because it reacts with LOX that is present in normal, healthy connective tissues. When the LOX in our connective tissues is inhibited, the result is osteolathyrism, a disorder that can lead to weak connective tissues and skeletal deformaties.5 To circumvent this drastic side effect, a method must be developed to deliver BAPN selectively to tumors.

One strategy to develop an inhibitor that can selectively target the LOX present in tumor cells is to design a prodrug. A prodrug is a molecule that is stable and inactive in the body, and then reacts to deliver its payload (in this case, BAPN) once it has reached the delivery site (e.g., the tumor). For example, once nitrobenzyl compounds (see image) reach a tumor cell, the lack of oxygen in the tumor causes them to react to release BAPN.6,7 Prodrugs capable of releasing BAPN have promising results, however few have been made and tested against LOX.7 This gap in research is what our project aims to fulfill.

Undergraduate research students in the Solano laboratory have already prepared several molecules that have the capability of selectively delivering the BAPN payload to tumor cells. Funds are needed to buy chemicals and supplies to synthesize more molecules. All research will be conducted by undergraduate students in the Department of Chemistry & Biochemistry at the California State University, Bakersfield (CSUB). Students will work under the close supervision of Dr. Danielle Solano.
The molecules synthesized as part of this project will be submitted to collaborators in Dr. Karlo Lopez’s research group for testing against the LOX enzyme.8 Molecules that significantly decrease the activity of LOX will be used to develop better inhibitors of LOX.
It expected the each student could prepare 2-3 molecules each academic quarter depending on the student’s course load and the complexity of the molecule. This will result in 32-48 new molecules at the end of the year, which will significantly increase our understanding of how to design an effective drug for the treatment of cancer metastasis.
REFERENCES
1. Erler, J. T.; Giaccia, A. J. Lysyl Oxidase Mediates Hypoxic Control of Metastasis. Cancer Res. 2006, 66, 10238-10241.
2. Erler, J. T.; Bennewith, K. L.; Nicolau, M.; Dornhofer, N.; Kong, C.; Le, Q.-T.; Chi, J.-T. A.; Jeffrey, S. S.; Giaccia, A. J. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 2006, 440, 1222-1226.
3. Narayanan, A. S.; Siegel, R. C.; Martin, G. R. On the inhibition of lysyl oxidase by β-aminopropionitrile. Biochem. Biophys. Res. Commun. 1972, 46, 745-751.
4. Bondareva, A.; Downey, C. M.; Ayres, F.; Liu, W.; Boyd, S. K.; Hallgrimsson, B.; Jirik, F. R. The Lysyl Oxidase Inhibitor, β-Aminopropionitrile, Diminishes the Metastatic Colonization Potential of Circulating Breast Cancer Cells. PLoS ONE 2009, 4, e5620.
5. Dawson, D. A.; Rinaldi, A. C.; Pöch, G. Biochemical and toxicological evaluation of agent-cofactor reactivity as a mechanism of action for osteolathyrism. Toxicology 2002, 177, 267-284.
6. Chen, Y.; Hu, L. Design of anticancer prodrugs for reductive activation. Med. Res. Rev. 2009, 29, 29-64.
7. Granchi, C.; Funaioli, T.; Erler, J. T.; Giaccia, A. J.; Macchia, M.; Minutolo, F. Bioreductively Activated Lysyl Oxidase Inhibitors against Hypoxic Tumours. ChemMedChem 2009, 4, 1590-1594.
8. Herwald, S. E.; Greenaway, F. T.; Lopez, K. M. Purification of high yields of catalytically active lysyl oxidase directly from Escherichia coli cell culture. Protein Expression Purif. 2010, 74, 116-121.


Biography

Chad Benavides, a senior at CSUB, is pursing his undergraduate degree in chemistry. After graduating this spring, Chad plans to prepare for the graduate school application process. He aspires to be professor and teach undergraduate organic chemistry.


Haley Hashim is a third year at CSUB majoring in chemistry with a concentration in biochemistry. Haley’s interest and fascination with the sciences has led her to declare a chemistry major. Her love and talent for science has motivated her to pursue a career where she can help people. Growing up, her family emphasized the importance in working hard toward your education. Science has always been fascinating to her, developing early on in her high school career. Classes in chemistry, physics and biology sparked Haley’s interest and helped her make logical sense of the world around her. Each course provided new and intriguing information to grasp daily.
Future fields she is considering are pharmacy or biochemical development, physician’s assistant, or forensic science. In addition to her love for science, Haley enjoys challenging situations that involve problem solving. Her organizational skills, coupled with her determination, help her face any problem until a workable solution is established. Recently, Haley joined the LOX project in Dr. Danielle Solano’s research group in summer 2014. Not only does Haley enjoy the research, she finds the project fascinating. This research has taught her discipline and the value of trial and error. Although the LOX project involves meticulous and hard work, the future outcome could be life changing.


Raymond Martinez is majoring in Chemistry, with a concentration in Biochemistry, and expects to graduate in spring 2016. Raymond is interested in Dr. Solano's medicinal research, particularly is the LOX project. His spark of interest comes from the organic chemistry reactions, such as the substitution with a substrate to form a product. Raymond plans on pursing a degree in pediatric medicine.


Nkiruka Oragwam is a junior at CSUB majoring in Chemistry with a concentration in Biochemistry and a minor in Biology. She plans to graduate in the spring of 2016 and continue her education in pharmacy school. Her interest in pharmaceutics and natural science courses, such as organic chemistry, is in line with the medically related research she does for Dr. Solano. She finds the research not only enjoyable, but also rewarding. She knows her work is contributing to a larger network of research geared towards helping people.


Dr. Danielle Solano is an assistant professor in the Department of Chemistry & Biochemistry at CSUB. She received her undergraduate degree in biochemistry at the California Polytechnic State University, San Luis Obispo and her masters in chemistry at Boston University. She conducted her doctoral work with Professor Mark Kurth at the University of California, Davis and joined the chemistry department faculty at CSUB in fall 2010. Dr. Solano teaches undergraduate organic chemistry and maintains an active research group of 8-12 undergraduate research students. In addition to research and teaching, Dr. Solano also coordinates a variety of community outreach activities designed to increase interest in science amongst local youth.


Expected project outcomes:
Students will use the results of their work to for their senior seminar papers and senior seminar presentations. Additionally if enough funds are raised to support student travel, the students will present their work at an American Chemical Society (ACS) National Meeting. It is anticipated that the results of this work will lead to a joint publication with Dr. Karlo Lopez’s research group in Cancer Research or the Journal of Medicinal Chemistry.


Will any products of the project be made available to donors?
We could provide copies of student PowerPoint presentations, student reports, student poster presentations, and (ideally) paper reprints.


Budget:
Supplies (list any items above $500. Smaller items can be combined as "General Supplies"): Chemicals $1000, General Supplies $500
Student stipend(s) (numbers of students and number of weeks):
Student Housing:
Student Travel (state destination(s) and purpose):
Other (please describe):
TOTAL: $1500
Matching funds (amount and source): The Department of Chemistry & Biochemistry will support this research by providing any chemicals/supplies available in the department stockroom and access to necessary equipment (400 MHz NMR spectrometer, GC-MS, FT-IR spectrometer, and gradient-HPLC).
TOTAL amount to raise on CREU: $1500


How will any additional funds be used?
Additional funds will be used for:
1) Student travel to regional and/or national meetings of the American Chemical Society to present the results of their research
2) Student stipends
3) Supplies to continue the project beyond one year

CREU recomends this proposal at the Highly Recommended level.

Reviewer Comments

" I believe their previous research experience will be a benefit for completing project proposed in this proposal - synthesize more similar molecules."

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