Our voices have been heard
Hunch #14- A Novel Epigenetic-PARP Inhibitor Combination to Inhibit Metastasis in Triple Negative Breast Cancer.
Richard Carpenter, Ph.D. / Kenneth Nephew, Ph.D.
This hunch brings together two unique areas of research, epigenetics and PARP inhibitors, to improve therapies available for triple negative breast cancer (TNBC), a highly aggressive form of breast cancer that occurs in 15-25% of patients. Epigenetics is the process by which cells control their function. Epigenetics describes the cellular proteins that tell genes what to do, where to do it, and when to do it. Cancer cells take advantage of this process and turn on genes in cells that stimulate growth, while turning off the genes that regulate and control growth. If we understand the process of epigeneitcs, we could utilize it in treatment, turning off what cancer has turned on. The other area of research this hunch encompasses is PARP inhibitors, a new class of drugs that treat cancer through accelerating DNA repair. These treatments have already proved to be very effective and provide less side effects for the women being treated; however, they are only effective in women with a BRCA genetic mutation. The goal of this hunch is to use the combination of epigenetics and PARP inhibitors to treat mice with breast cancer, and determine if this combination will be a viable treatment option for women with TNBC who do not have the BRCA mutation.
Hunch #15- Identification of “Tumor Compaction Factor X” in a Bone Microenvironment for Preventing Bone Metastasis from Breast Cancer
Hiroki Yakota, Ph.D.
The researchers leading this pilot project expect it to open a new avenue to prevent metastatic breast cancer. Bone is a common site for breast cancer to move and is often the first site where a recurrence of breast cancer is identified. In addition to being common, bone metastasis often causes great pain for patients, reducing their quality of life. This hunch hopes to answer the questions: Why does breast cancer frequently metastasize to bone? Does bone emit a special chemical signal that attracts breast cancer cells? And can we block this signal and protect bone? Our researchers recently conducted real-time filming of bone-tumor interactions, which show osteocytes, the most abundant type of bone cells, interact with and cling to breast cancer cells like a magnet. This attraction seems to be induced by an unknown secretory protein factor from the osteocytes. In this newly funded project, our researchers will work to identify the chemical and biological nature of the protein the osteocytes are releasing through mass spectrometry. Once the protein is determined, we should be able to explain why breast cancers tend to hone in on bone. This knowledge could be used to develop novel treatements for preventing bone metastasis and could significantly improve the efficiency of drug delivery for breast cancer patients.
Hunch #16- Correlative Studies on a Phase I Trial of Gedatolisib Plus PTK7-ADC in Metastatic Triple Negative Breast Cancer
A Clinical Trial Made Possible by 100 Voices of Hope
Milan Radovich, Ph.D.
The preclinical trial data to support the initiation of this trial were made possible by 100 Voices of Hope’s funded Hunch #4. Triple negative breast cancer (TNBC) is a devastating disease with poor outcomes and a lack of effective therapies. Typical treatment for TNBC usually entails administration of a variety of chemotherapies given as single-agents (one at a time) for as long as the tumors are kept at bay or are shrinking in size. Unfortunately, single-agent therapy is not always clinically effective. Many TNBC patients progress through multiple drugs and eventually end up succumbing to the disease. We have come to learn that resistance to single-agent therapy is common due to these tumors activating compensatory pathways. Imagine the inside of a tumor cell like a complex electrical wiring diagram - when one node is shut down, the current will reroute. Likewise, when a key survival pathway (known as the PI3K pathway) is shut down by a drug, these tumors can rapdily reroute, activating another pathway (known as the Wnt pathway) that promotes tumor growth and survival. Targeting both of these is comparable to a game of whack-a-mole. Through extensive preclinical experimental testing, however, we have demonstrated the potential of two therapeutics, Gedatolisib and PTK7-ADC, for targeting both the PI3K pathway and the Wnt pathway simultaneously. This year, we initiated a Phase 1 clinical trial combining Gedatolisib and PTK7-ADC for patients with metastatic triple negaitve breast cancer. The endpoints of this trial are to determine the safety of the combination and to observe early signals of clinical efficacy as determined by tumor response rate and patient survival. So far, eight patients have receieved the trial treatment drugs and five more are expected to join shortly.
However, the story does not end there. 100 Voices of Hope has continued to support this important effort, through choosing to fund this year's Hunch #16. This hunch will allow us to analyze all the data that comes back from the clinical trial. This will help us better understand the biology of which tumors respond to the new treatment and why some tumors can resist it. The primary outcome of this hunch is to use this data to support a larger Phase 2 trial of the combination and advance its clinical development. Our long-term goal is to provide a new FDA-approved cutting-edge treatment for metastatic TNBC patients.
With help from your seed funding, Dr. Radovich and his team of researchers recently received a National Cancer Institute grant to even further expand this project.
Hunch #12 - A Novel Approach to Discover Drug Resistance Genes in Metastasized Breast Cancer Cells - Funded in memory of Carrie Glasscock West
Led by Tao Lu, Ph.D., and Lang Li, Ph.D., this hunch addresses the problem of drug resistance, the greatest challenge for the successful treatment of metastasized breast cancer. To date, no effective approaches have been developed to overcome drug resistance. Drs. Lu and Li hypothesize that high expression of some key proteins leads to drug resistance in metastasized breast cancer. Recently, their lab has developed an extremely innovative technique called validation-based insertional mutagenesis (VBIM), for novel gene discovery. This project uses the VBIM technique to identify key proteins that lead to chemotherapy resistance in metastasized breast cancer cells. The researchers will analyze a panel of clinically used drugs with different cell killing mechanisms to perform the experiments. Overall, this unique and comprehensive approach could give physicians the important information they need to design more rational and precise therapies with greater effectiveness for breast cancer patients.
Hunch #13 - Biology of Breast Cancer Health Disparity
The goal of this hunch is to answer the critical biological question of why breast cancer presents differently among different groups of women. Although breast cancer is less common among African American women when compared to Caucasian women, the outcomes for African American women are generally poor, even after considering socioeconomic and healthcare access issues. By contrast, Hispanic women develop less aggressive breast cancers and have better outcomes. Through understanding the biologic differences between normal breast tissues of different ethnic groups, we may be able to decipher reasons for this health disparity. This hunch will allow a group of researchers to obtain sufficient preliminary results to develop a multi-million dollar project proposal that will be submitted to the National Cancer Institute by early 2018. IU is the only place with resources to address these questions because of the availability of more than 5,000 normal breast tissue samples through the Komen Tissue Bank. The goal of this project is to identify the genetic factors that make cancer more or less aggressive. This could help to better characterize tumors in all women and lead to improved treatment of breast cancer in the future.
Hunch #10 in memory of Mary Corbett
Hunch #10 is spearheaded by Drs. Jian-Ting Zhang, Jing-Yuan Lui and Hal Broxmeyer. It focuses on triple negative breast cancer and immunotherapy, a very promising area in cancer research where drugs are used to train our own bodies to attack aggressive tumors. The team is working on finding an alternative to a very effective immunotherapy drug – pembrolizumab – that Jimmy Carter received recently. Finding an alternative is key because the cost of pembrolizumab exceeds $1 million a year. Dr. Jian-Ting Zhang and his team will screen a library of FDA-approved drugs to look for matches, with the goal of identifying an alternative that is easy to make and has already been demonstrated as safe in humans. They hope to close in on a drug within the funding period and move it to clinical trial as quickly as possible. With so few effective options for treating triple negative breast cancer, these studies are extremely important to find solutions that can move to clinical trial more quickly.
Hunch #11 in memory of Anne Abernethy
Hunch #11 was proposed by Dr. Milan Radovich and focuses on triple negative breast cancer. He and his team plan to test two FDA-approved drugs in mice with triple negative tumors that have shown great potential for being an effective combination. If they receive positive results, this hunch would be used to support the launch of Phase I/II clinical trials. Dr. Radovich's hope is that this combination will provide a new “precision medicine” based drug combination for triple negative breast cancer.
The winning hunch for 2015 is innovative in two ways. It is the first collaborative project we’ve funded with a team of Purdue biomedical engineers. Second, this hunch applies to all types of metastasis and focuses on developing a microfluid device that can circulate in the bloodstream and destroy metastatic cancer cells as they migrate.
The team of researchers includes Dr. Hiroki Yokota, biomedical engineer; Dr. Likhun Zhu, mechanical engineer; Dr. Sungsoo Na, biomedical engineer; Dr Jong Eun Ryu, mechanical engineer; and Dr. Mangilal Agarwal, Associate Director of Research Development. Dr. Yokota also works with Dr. Hari Nakshatri on Hunch #8.
The purpose of the project is to create a microfluidic device that senses metastatic cancer cells in the bloodstream and destroys them. Specifically, the device will detect cell wall stiffness, which is different in cancer cells versus normal cells. This is proof-of-concept funding, meaning that we are funding the idea at its beginning stages – the hardest time to attract support. As we move forward in cancer research, more collaboration between the physical sciences including engineering and the biological sciences including chemistry is pivotal. Both sides offer unique perspectives in how we can treat and stop metastasis, which is the primary reason people lose their lives to cancer.
- Developed prototype device that is going to be manufactured and tested in the next six months
- Received two grants from IUPUI totaling $30,000 to grow this research
Drs. Hari Nakshatri and Hiroki Yokota received approval from the Institutional Animal Care Approval Committee after our May update and are now beginning a pilot experiment of guanabenz, a drug shown to kill breast cancer cells and strengthen bone cells, on 15 animals. By October, they will have the first results of this trial. In addition to the animal trial, Dr. Yokota’s group is researching guanabenz at a cellular level to see if it and other chemical agents can prevent bone metastasis by blocking kinase activity. Blocking kinase activity in malignant cells helps stop bone metastasis in breast cancer. Dr. Kathy Miller also received a grant from the Breast Cancer Research Foundation to study guanabenz with patients.
The drug – guanabenz – has been shown to kill breast cancer cells and stop the spread of breast cancer cells to bone in the laboratory. However, persistent bone pain experienced by patients with bone metastasis is largely due to bone loss. Guanabenz is also shown to prevent bone degradation and promote new bone formation, which will help to alleviate pain.
This hunch proposes to validate guanabenz’s anti-cancer and bone-strengthening effects in a formalized laboratory study. The team’s goal is to develop data to initiate clinical studies with this drug to demonstrate prevention and treatment of bone metastases and to rebuild bones damaged by cancer.
- 100 Voices of Hope funding has allowed for an animal trial of guanabenz, a drug that kills breast cancer cells and strengthens bone cells. Animal trials are a necessary precursor to clinical trials.
- Dr. Kathy Miller received a $200,000 grant from the Breast Cancer Research Foundation, $70,000 of which will supplement this research with a clinical trial of guanabenz.
Dr. Sunil Badve is studying a group of metastasis suppressor genes (MSGs) that are thought to play an important role in preventing the development of metastases. In experimental models, turning off the MSGs increases the frequency and size of metastasis, and human tumors that have turned off the MSGs have a worse prognosis. Unlike some other cancer genes, the MSGs are not “mutated,” they are just turned off. Since the last update in May, the logistics of the projects have been mapped with a start date of September anticipated. The main question this research is trying to answer is: How do cancer cells turn off MSGs?
Until recently it has been hard to study the regulators (called long non-coding RNA, or lncRNA for short) of these genes, but new technology makes this possible. First, Dr. Badve will use data from the Cancer Genome Atlas, an NCI-sponsored project including genomic data from almost a 1,000 breast cancer patients, to identify lncRNAs associated with metastasis. After confirming those leads in tumors from the breast cancer program, it will be determined if those same lncRNAs turn off MSGs and increase metastasis in mouse models. Finally, a large number of FDA-approved drugs that may turn the MSGs back on and prevent the development of the metastasis will be analyzed.
- To target drug treatment for a breast cancer tumor it is critical to identify how cancer cells work and metastasize. This research focuses on how cancer cells turn off genes that prevent metastasis.
Dr. Samy Meroueh is developing drugs for the prevention and treatment of metastatic disease by targeting a protein that is exclusively expressed by malignant tumors. Since the last update in May, he has submitted his findings to be published in the American Chemical Society Chemical Biology Journal, a highly influential journal in chemical biology. He has also collected enough data from 100 Voices of Hope funding to submit a new NIH proposal to continue his research.
He is following a chemical method to develop a targeted drug that kills malignant tumor cells and spares healthy cells. A new compound named IPR1110 – discovered in his laboratory – targets a protein called uPAR that is only present in malignant cells. His lab is the only one in the world that has developed a small molecule than can attach to uPAR. The lab is working to chemically link IPR1110 to a chemotherapeutic so that when the molecule attaches to uPAR it delivers the drug to malignant cells. The main question his research is trying to answer is whether IPR1110 can attach to uPAR successfully and deliver the chemotherapeutic to destroy malignant cells while excluding healthy cells.
Dr. Meroueh anticipates that the molecule IPR1110 may also act as a stand-alone agent for the treatment of metastasis. His recent data verifies that IPR1110 can be used as both a homing agent to deliver a chemotherapeutic and may be useful as a therapeutic agent. With 100 Voices of Hope funding, he has been able to make the targeting agent as effective as the drug to which he is linking. His next steps include animal testing in December and January to assess the effectiveness of the compound.
- Dr. Meroueh used 100 VOH funding to develop data that was submitted to the American Chemical Society Chemical Biology Journal, the second most influential journal in chemical biology.
- With the data collected from 100 VOH funding, he also plans to submit a new NIH proposal to expound his research.
- He developed a new compound, the only one of its kind in the world, that may be used to deliver chemotherapy to malignant cells without harming normal cells.
- The compound he developed may also be able to treat metastasis in addition to delivering chemotherapy.
Dr. Milan Radovich sequenced the genomes of 135 patients with triple negative tumors being treated with a new drug combination and presented his finding at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO). Those results demonstrated a druggable pathway and RNA biomarkers that mediate chemotherapy resistance in triple negative tumors. Dr. Radovich is currently sequencing the plasma from the trial which allows for sensitive detection of treatment response and relapse in patients.
In collaboration with industry, Dr. Radovich has early access to a diagnostic tool that will allow his lab to detect circulating tumor DNA with an extremely high sensitivity. They are also in the early phases of developing a new analysis method for circulating RNA biomarkers in anticipation of submitting an NIH proposal specifically for RNA biomarkers for early cancer detection. This work has identified novel mechanisms of why triple-negative breast cancers can become resistant to chemotherapy in newly diagnosed patients. Patients who have residual tumors after chemotherapy have a high recurrence rate. Further, the data is informing the laboratory of new therapeutic interventions for those patients who develop resistance.
- 100 VOH funding led to a presentation by Dr. Radovich of his research at the American Society of Clinical Oncology in June.
- He is preparing to use the data collected to submit an NIH proposal to research RNA biomarkers for the early detection of triple-negative breast cancer.
Dr. Milan Radovich is in the final phase of completing the mouse studies in collaboration with industry using a novel drug combination for triple-negative breast cancer. The two-drug combination has been so successful that treatment to mice had to stop so that researchers would have enough residual tumor to analyze. A final anti-tumor efficacy study of the drug combination is being tested in mice with implanted human tumors to see if the response to treatment remains effective. Dr. Radovich has been invited to submit an Investigator Initiated Trial grant request with the hopes of opening a Phase I trial in metastatic triple negative breast cancer within six months.
- Dr. Radovich’s lab found a new drug combination that significantly reduced triple negative breast cancer tumors in animals. In collaboration with industry, this 100 VOH-funded research will be moving into a clinical trial within six months.
- He presented research at the Annual San Antonio Breast Cancer Symposium in December 2013.
Drs. Sunil Badve and Yesim Gökmen-Polars’ project is progressing along two fronts. The project goal is to determine genes that are involved in the late recurrence of breast cancer, particularly estrogen receptor (ER) positive breast cancer. Breast tissue taken at the time of diagnosis is being compared with tissue from women who are taking hormonal therapies at five and 10 years out to learn which genes are being expressed.
The first part of the research focuses on the biomarker ESPR1 and its role in endocrine resistance. Endocrine therapy is an important part of ER-positive breast cancer treatment; patients sometimes develop resistance leading to late recurrence. It has been found that in patients with endocrine resistance, there is a higher expression of ESRP1, resulting in poor outcomes. Drs. Badve and Gökmen-Polar are drilling further down into the gene sequencing to identify a druggable target to overcome endocrine resistance.
The second part of the research involves a genetic analysis of tumors from 2,000 patients with ER-positive breast cancer. This provides a very thorough breakdown of genetic differences between tumor types. Knowing the gene pathways in tumors that lead to late recurrence will give Drs. Badve and Gökmen-Polar a picture of genes that can be targeted for therapeutics.
- Research related to identifying gene markers that indicate endocrine resistance in ER-positive breast cancer was recently accepted to be published in Modern Pathology, a highly ranked and influential international journal.
- Drs. Badve and Gökmen-Polar presented findings at the 2013 Annual San Antonio Breast Cancer Symposium and at the 2014 American Association of Cancer Research annual meeting.
Hunch #1 and #2
Dr. Hari Nakshatri identified a potential biomarker for recurrent breast cancer in circulating blood; he patented his biomarker and secured a $400,000 National Cancer Institute-funded grant to expand the project. While this project has been successfully completed, his research continues and is focusing on how to improve cardiac function in breast cancer patients. He is seeking grant funding. His initial work on this biomarker was published in Breast Cancer Research (2011 13: R86) and additional studies in Cancer Research (2014 74:4270-81).