History

Rock River Cancer Research Foundation
April 2017 – Update on Funding

“Targeting SmgGDS in Breast Cancer Using Antisense Drugs”
Carol Williams, PhD, Professor of Pharmacology and Toxicology
Funding: October 2015 – $50,000 Total

Research Description: Dr. Williams’ research focuses on a protein called SmgGDS that is made in high amounts by breast cancer cells and helps breast cancer cells multiply and form tumors. She and her colleagues previously found that breast cancer cells make two different forms of SmgGDS, which are called SmgGDS-558 and SmgGDS-607. Both SmgGDS-558 and SmgGDS-506 help the cancer cells multiply and form more tumors. Dr. Williams’ research is focused on identifying compounds that lower the amounts of SmgGDS-558 and SmgGDS-607 in breast cancer cells, so the cancer cells cannot use SmgGDS to form tumors. Once these compounds are identified, they could potentially be used to treat breast cancer. In this specific project, Dr. Williams is collaborating with Dr. Mark McNally, who studies how cells make multiple forms of specific proteins, to find ways to effectively lower SmgGDS-558 and SmgGDS-607 in breast cancer cells, and slow the growth of the cancer cells. Dr. Williams is testing compounds called “antisense oligonucleotides” (ASOs) that alter the levels of SmgGDS-558 and SmgGDS-607 in breast cancer cells. This project takes the next step in determining if these ASO compounds will decrease the ability of breast cancer cells to form tumors and if they could potentially be used in breast cancer therapy.

Update Since November 2016 Report:
 Publications/Abstracts/Posters: Dr. Williams published a scientific report in the December 4, 2016 issue of Journal of Molecular Biology describing the molecular mechanism that SmgGDS uses in breast cancer cells to regulate two closely related proteins called Rap1A and Rap1B. These two related proteins are called “small GTPases”, and they help breast cancer cells adhere to one another. When breast cancer cells adhere to one another, the cancer cells have less ability to leave tumors and spread through the body during metastasis. The diagram shown below is from this publication, and it summarizes the findings that are presented in this publication. It depicts Dr. Williams’ discovery that SmgGDS-607 binds Rap1A and Rap1B, and helps Rap1A and Rap1B undergo the biochemical process called prenylation. This prenylation event helps Rap1A and Rap1B move to the membrane of breast cancer cells. Once Rap1A and Rap1B are at the cell membrane, the breast cancer cells adhere to one another and have reduced ability to metastasize. This discovery is important because it helps define one of the roles that SmgGDS plays in reducing metastasis of breast cancer.

 Budget Performance/Special Needs: We are on track using the budget, and no unanticipated expenses have been encountered.

 Original Research Goals: Aim 1. Test the hypothesis that the prenylation and trafficking of small GTPases, and the malignant phenotype of cultured breast cancer cells, will be diminished by exposing the cells to newly identified antisense oligonucleotide (ASO) drugs that alter SmgGDS pre-mRNA splicing. We will compare how ASOs that disrupt SmgGDS pre-mRNA splicing affect the following events in cultured breast cancer cells: A)
prenylation and membrane targeting of GTPases, and B) cell survival, proliferation, and cell cycle progression.

Aim 2. Test the hypothesis that tumorigenesis of human breast cancer xenografts in mice will be diminished by treating the mice with ASOs that alter SmgGDS pre-mRNA splicing. We will compare how the ASOs that disrupt SmgGDS pre-mRNA splicing affect tumor growth, the expression of SmgGDS in the tumors and normal mouse tissues, and the physiological state of the mice.

 Progress Toward Goal:
Aim 1. Our recent publication (described above) has improved our understanding of how SmgGDS interacts with small GTPases such as Rap1A and Rap1B to promote breast cancer metastasis. We are now determining which ASO most significantly alters the interaction of SmgGDS with Rap1A and Rap1B and other small GTPases, and which ASO has the greatest inhibitory effects on breast cancer cells. We have identified a specific ASO (named ASO A11) that significantly inhibits the proliferation and cell cycle progression of cultured breast cancer cells. In contrast, other ASOs that we developed have less of an effect on the proliferation and cell cycle progression of the breast cancer cells. These results indicate that ASO A11 is the
best candidate to use in the mouse studies that will be conducted in Aim 2.
Aim 2. To conduct the mouse studies, we need to modify the breast cancer cells to allow us to detect the cancer cells inside the mice while the cancer cells are forming tumors. This modification involves engineering the cells to make a protein called “luciferase”, which can be detected inside living mice using our specialized imaging system. We are currently making these modifications to the breast cancer cells, so they will make luciferase. Once we have determined that the breast cancer cells are making enough luciferase to be detected by our imaging system, we can start conducting the mouse studies outlined in Aim 2 to test the ability of ASO A11 to inhibit breast cancer cells from forming tumors in the mice.

 Ultimate Goal: Determine if these ASO compounds could be used as a way to decrease the ability of breast cancer cells to form tumors.

 Personal Remarks: In October, 2016 I was the guest speaker at the Biological Sciences Seminar at Carnegie Mellon University in Pittsburgh. I spoke about our studies of SmgGDS in breast cancer, and I was very pleased when Dr. Mathias Losche asked us to collaborate with him to conduct structural studies of SmgGDS. Dr. Losche is an internationally recognized expert in biophysics and structural biology, and we are verypleased to be working with him to define how SmgGDS interacts with cell membranes to promote cancer.

 

Rock River Cancer Research Foundation
April 2017 – Update on Funding

“Image Guided NIR Light Based Interventions for Metastatic Breast Cancer”
Amit Joshi, PhD, Associate Professor of Radiology

Funding: October 2015 – $50,000 Total
Research Description: In this study, Dr. Joshi and his colleagues are researching ways to use nanoparticle therapy to kill breast cancer cells that have spread to the liver. Gold-based nanoparticles, which are visible with X-ray CT, MRI imaging, and optical imaging, are injected directly into the arteries feeding the liver metastases. Near-infrared light then is used to heat the nanoparticles, and this heat kills the cancer cells. Dr. Joshi and his colleagues are researching how to adapt this therapy for use in breast cancer that has metastasized to the liver. This therapy could address some of the side effects and limitations in current breast cancer treatments.

Update Since December 2016 Report:
 Publications/Abstracts/Posters: Abdul Parchur, PhD submitted an abstract on “Site-Selective Delivery of Novel Trimodal Optical/MR/X-Ray Contrast Bearing Photothermal Nanoconstructs to liver metastasis” to WCIO 2017 (World Conference on Interventional Oncology). The abstract was accepted and selected as the “Best Abstract for 2017,” and it will be presented in the plenary session of the conference in June 2017 in Boston. This prestigious conference promotes dialogue and collaboration among some of the top interventional oncologist in the world. Prominent scientists, faculty, postdoctoral fellows and graduate students gather together to collaborate and share insights in areas experiencing rapid scientific advances and conducting cutting-edge research.

 Budget Performance/Special Needs: Budget performance is on track. We expect to use all allotted funds in the project period.

 Original Research Goals:
 Aim#1 Develop and validate NIR fluorescence, CT, and MR image guided nanoparticle and therapeutic light delivery system, agents, and methods in tissue phantoms and rat models of breast cancer liver metastasis.
 Aim#2 Investigate the impact of tumor-host microenvironment variation on the bio-distribution of nanoparticles delivered in a site-specific manner, and the efficacy of photo-thermal therapy.

 Progress Toward Goal:
Aim#1: We have synthesized ~70 nanometer gold nanorods coated with gadolinium and modified to silently circulate in body, while trapping in tumors. The nanorods were tested for X-ray CT imaging and MRI imaging in both human and animal imaging scanners. We also tested the rods in a rat model of liver metastasis. The results are under preparation for submission to “Nanomedicine and Nanobiotechnology Journal”.

Aim#2: We tested the impact of varying host (i.e. individual patient) environment on the accumulation of gold nanorods in triple negative breast cancer, and determined that genetic variation in hosts plays a big role in response to photothermal therapy for breast cancer. Confirmatory experiments are undergoing and we expect to report concrete results in the next quarter.

 Ultimate Goal: Develop more effective treatments with minimal harsh side effects to treat breast cancer that has metastasized to the liver while reducing harsh side effects.

 Personal Remarks: As part of conducting this research and discussions with collaborators, we struck upon new ideas about using the nanoparticles developed under Rock Foundation support for imaging and therapy of patient derived breast cancer xenografts in novel human mimicking mouse models developed by Dr. Hallgeir Rui, who is the Breast Cancer Program Co-Leader at MCW. This information contributed towards submission of a program project application to that National Institutes of Health targeted to therapy resistant Estrogen Receptor positive breast cancer.

2015 

RTAC_Saturday_2015_175RTAC_Saturday_2015_194

We gave a $100,000 grant donation to the Medical College of Wisconsin for two (2) grants.  One for $50,000 and one for $50,000. Both grant awards were presented at the 21st Annual “Ridin’ To A Cure” breast cancer ride in September of 2015.

2014 

donation

$75,000 Grant Recipient Dr. Carol Williams
and the Medical College of Wisconsin.

The Rock River Cancer Research Foundation recently awarded $75,000 to Carol Williams, Ph.D., professor of pharmacology and toxicology at the Medical College of Wisconsin (MCW) for her research “SmgGDS as a Novel Therapeutic Target in BreastCancer.”  Board members from the Rock River Cancer Research Foundation came to MCW to present a check to Dr. Williams and Dr. Ming You, MCW Cancer Center Director.  Shown here (left to right) are: Woody West, Dr. You, Vicki Volp, Ed Stein, Dr. Carol Williams, Debbie Gast and Michelle Luckiesh.  Debbie Gast is president of the Rock River Cancer Research Foundation.  Other board members are Mary Mueller, Janet Abraham, Dr. Kelli Pettit, Anne Towne and Pam Fisher.

The Rock River Cancer Research Foundation raises its funds through its annual “Ridin’ to a Cure” motorcycle ride and party, which will take place on September 27.  This year marks the 20th anniversary of the event. For more details or to register, see: http://www.ridintoacure.com/

About the Medical College of Wisconsin

The Medical College of Wisconsin is the state’s only private medical school and health sciences graduate school.  Founded in 1893, it is dedicated to leadership and excellence in education, patient care, research and community engagement.  More than 1,200 students are enrolled in the Medical College’s medical school and graduate school programs in Milwaukee.  New regional medical education campuses are opening in Green Bay in 2015, and in Central Wisconsin in 2016, with each recruiting initial classes of 15-20 students.  A major national research center, MCW is the largest research institution in the Milwaukee metro area and second largest in Wisconsin.  In FY 2012-13, faculty received approximately $160 million in external support for research, teaching, training and related purposes, of which approximately $144 million is for research.  This total includes highly competitive research and training awards from the National Institutes of Health (NIH).  Annually, College faculty direct or collaborate on more than 2,000 research studies, including clinical trials. Additionally, more than 1,350 physicians provide care in virtually every specialty of medicine for more than 425,000 patients annually.