What’s in a hunch? Every year, the 100 Voices of Hope organization invites the experts at IU Simon Comprehensive Cancer Center to explore their “hunches” on new ways to treat, diagnose, and prevent breast cancer—and your gifts help fund their research.
Triple negative breast cancer (TNBC) is a challenging form of cancer that doesn't respond well to traditional treatments. Immunotherapy is a promising approach that involves using the body's immune system to fight cancer. One type of immunotherapy uses special immune cells called gamma delta (γδ) T cells, which have unique abilities to recognize and attack cancer cells. However, there are challenges, such as finding the right targets on cancer cells for these immune cells to attack effectively. In this project, we are using tiny particles released by cancer cells called exosomes to help identify these targets on TNBC cells. These exosomes carry information about the cancer cells' surface proteins. Previously we studied interaction of TNBC exosomes with T cells and discovered specific codes that can guide γδ T cells to target TNBC cells effectively. In the next phase of this project, we will use advanced gene-editing techniques to modify γδ T cells. We will insert specific codes into the γδ T cells, essentially arming them with the knowledge to recognize and destroy TNBC cells. Our team will then carefully test these genetically engineered γδ T cells to observe if they may effectively kill TNBC cells.
Breast cancer is a highly variable disease. Immune checkpoint inhibitors are a type of immunotherapy that uses the immune system’s natural ability to fight cancer. Immune checkpoint inhibitors have been effective in the treatment of about 40% of triple negative breast cancers that express the protein PD-L1. We take a different approach to immune therapy. Rather than infusing a lab-made antibody, we propose a vaccine that triggers the body’s B-cells to produce the right antibody that will attack the cancer cells. This approach has several potential advantages, including: (1) tumor specificity; and (2) activation of immune responses against other proteins that are selectively expressed by tumor cells. We have already tested a vaccine against HER2 in an early clinical trial. The results were encouraging with minimal toxicity and prolonged production of HER2-targeted antibodies. We have now developed a portfolio of several immune checkpoint vaccines (PD-1, PD-L1, CTLA-4, TIGIT and LAG 3) that are intended to be used in combination immunotherapies. Unlike monoclonal anti-PD1 antibody therapy, a combination vaccine therapies (chimeric B-cell peptide) proposed in our project are designed to stimulate a sustained immune response with minimal toxicity. We have prioritized TIGIT (one of our developed immune checkpoint vaccines) as a target of immunotherapy for invasive breast cancer to be used in combination with other vaccines for both triple negative and HER2+ disease. The proposed preclinical studies will be used to test these combinations prior to planned phase 1 clinical trials.
Cancer cells have many tricky ways to avoid the immune system and become resistant to treatment. All cells have proteins on their surfaces – and changing these proteins can impact the immune system’s ability to recognize the cell and may impact the response to antibody-based treatments. Very recently, we’ve learned that in patients with metastatic breast cancer, The proteins on tumor cells contain more of a specific sugar molecule (called FAGL1) to their surface proteins. When more of these sugars are present, the disease presents as more aggressive – and survival rates decrease. The sugar molecules make it hard for antibodies to recognize the tumor, and they also promote inflammation and growth in the tumor. The goal of this research proposal is to use a technique called mass spectrometry to identify which cell surface proteins carry the FAGL1 modification in breast cancer cells growing in the lab and on patient tumor samples. Then we will study whether blocking this sugar molecule could be useful as a breast cancer therapy.
Our immune system recognizes and attacks foreign pathogens (bacteria, viruses) as well as tumors. The immune system has several different kinds of cells with very specialized functions. T cells are a part of the immune system that focuses on specific foreign particles. T cells play a critical part in immunity to foreign substances. Each T cell recognizes only one target – your body makes hundreds of thousands of T cells that are never used. When a T cell recognizes its target, it begins the attack. It also suppresses immune cells called (Tregs) that would stop the attack.
In this project, we will study the role of exosomes (tiny bubbles that pinch the cell membrane) that carry messages to stop the immune response. These tiny particles can find their way to the target immune cell using their specific surface proteins. They carry unique messages including RNA, DNA, or protein signals that impact the function of the target cell. Recently, we have seen a very specific interaction between metastatic breast cancer exosomes and T cells. We will use powerful new technology to study the messages in exosomes from individual breast cancer cells, sequencing the message in one exosome at a time. We are hopeful that this detailed study would lead us to identify potential molecules and genes that regulate the immune response. Once we’ve identified the messages that inhibit the immune response, we will engineer T cells that lack that critical function so we can study how to turn the function back on. We believe that the successful development of more potent engineered T cells would help us provide non-invasive therapies for both early and late-stage metastatic breast cancer patients.
Communication is a commodity in the 21st century. What is true in our society is also true at the molecular level in tumors. Central to the development of cancer and the movement of cancer to distant parts of the body is the ability of cells to communicate. In fact, the communication among cells in the immune system within the local tumor environment determines the rate of tumor growth and the ability of the tumor to metastasize. Current immune-based therapies, such as the anti-cancer drugs routinely advertised on television, have had remarkable impact in lung cancer. These immune therapies were developed by targeting “off signals” communicated between immune cells. This hunch is based on one of those “off signals” called a cytokine – a molecule that is tossed into the environment by one cell as a means of communicating to other cells. We found that blocking this cytokine, called IL-9, impairs the ability of metastases to form in the lung, a common site of tumor spread. We further found that the cells in the lung that respond to IL-9 share features with cells in the breast tumor. The studies in this proposal will test the effects of blocking IL-9 alone or in combination with other standard of care therapies for breast cancer. We will further test whether blocking the signal triggered by IL-9 controls tumor growth and metastasis. The work would provide the basis for several approaches to translation into patients. First, IL-9 blocking antibodies were developed and tested in clinical trials for asthma years ago. They have never been tested for efficacy in cancer. Second, drugs that block the signals triggered by IL-9 are being used in the clinic for a variety of autoimmune and allergic diseases. Our data suggests they might also be useful in modifying responses to tumor. Finally, the cells that contribute to IL-9 production can be targeted to modify immune responses. The proposed studies will lay the foundation for using therapies already developed for other purposes as an adjuvant to breast cancer treatment.
The road to a cure starts with learning how and why breast cancer develops, how it behaves at different stages of a woman’s life, and how it uniquely affects women from different racial and ethnic groups.
Recent advances in genomic research raised hope of identifying a specific genetic abnormality in cancer metastasis that differentiates it from the primary tumor. The hope was we could take advantage of this abnormality to specifically target metastasis.
Unfortunately, that approach hasn’t worked, despite sequencing metastatic tissues from multiple organs from the same donor and sequencing the primary tumor and metastasis from the same patient. Now we must think about the metastatic process differently.
One possibility is that the ability to metastasize is hardwired in the primary tumor from the beginning. If that is the case, we won’t find it by comparing primary to metastasis. Instead, we need to look for genetic abnormalities in the primary tumor that enable metastasis.
In our studies, we found that when breast cells obtained from a healthy donor were made cancerous upon introduction of one genetic abnormality (oncogene) they developed tumors in mice that did not metastasize to lungs. However, cells from the same donor when made cancerous by a different oncogene, developed tumors that did metastasize to lungs
When we compared proteins in the primary tumor and metastasis from the second model, there were minimal differences—just like the human studies. Our hypothesis is that cells that became cancerous by the second oncogene but not the first oncogene secrete proteins that are released into the bloodstream.
These proteins then go to the lung and modify the lung in such a way that it becomes hospitable for the cancer cells to come, attach, and grow. In other words, these proteins make a section of lung “breast-like” so that breast cancer cells feel at home.
Through sophisticated techniques of proteomics, we would like to identify those proteins that are expressed differently in our models and determine how they modify the metastatic site to welcome cells from the primary site. These efforts should lead to the development of new drug targets for metastasis.
Samy Meroueh, PhD
Healthy cells hold on tightly to the cells next to them. When they lose contact with their neighbors, they die. Cancer cells need to let go of their neighbors to move into the blood stream and metastasize. How do cancer cells let go without dying?
Proteins known as YAP and TAZ protect cancer cells from dying when they are ‘on their own’. YAP and TAZ also suppress the immune system’s ability to recognize and kill the cancer cells. In healthy cells that are in contact with their neighbors, YAP and TAZ are turned off. The goal of this proposal is to turn off YAP and TAZ in cancer cells.
Rather than developing a drug to interact with the proteins and inhibit their function, this group takes a different approach, using PROTAC degraders, a new technology that could revolutionize cancer drug development. Several PROTACs have been approved for clinical trials. PROTACs take advantage of the cell’s own recycling machinery to degrade or eliminate the target, in this case YAP and TAZ.
The lab has developed a PROTAC degrader that is capable of eliminating YAP and TAZ from triple-negative breast cancer cells at nanomolar (really low) doses. We expect our PROTACs to prevent triple-negative breast cancer metastasis in animal studies. Because PROTACs are catalysts, and they do not compete with their target, very small doses are required for treatment, making them much easier to develop into drugs for patients.
Funding will enable us to test our existing PROTACs (TED-650 or TED-674) in animal studies of cancer metastasis. If successful, the PROTACs will become candidates for investigational new drug studies and eventually clinical trials for the prevention and treatment of cancer metastasis, and for combination studies to inhibit tumor growth.
Sunil Badve, MD and Yesim Polar, PhD
There is no targeted therapy for patients with triple negative breast cancer (TNBC), one of the most aggressive forms of the disease. The use of chemotherapy prior to surgery can lead to a dramatic reduction in tumor size or even complete disappearance of a tumor, which is called pathologic complete response or pCR. pCR is associated with excellent long-term survival.
To understand the biologic basis of pCR, this lab has compared gene expression patterns (think of them as gene fingerprints) in patients who achieved a pCR with chemotherapy and those whose tumors were resistant. This led the team to identify “ion transport” as a major pathway associated with chemotherapy resistance.
This hunch will target the ion transport pathway as a way to control metastatic TNBC. ‘Ion transport’ is a major way cells carry information from inside to outside the cell, and vice versa. Think of it as the information highway for cells.
Cancer cells foul their immediate environment and make it very acidic for normal cells. This acidity is controlled by ion-transporters. We can alter the levels of these transporters either by genetically manipulating the cells or by treating them with drugs.
Recently, this team collaborated with a researcher at the University of Oxford who documented that S0859, a drug that disrupts ion transport, alters acidity in the cancer cell’s environment and suppresses tumor growth. The Oxford study was conducted in 10 cell lines, and only one was a TNBC cell line.
Funding this hunch would allow our researchers to investigate the utility of S0859 in a broad range of TNBC cell lines and patient-derived animal models.
Hiroki Yokota, PhD
Survival of the fittest is a dominant principle in nature. Fish compete for food and the best habitat in the ocean; trees compete for water, nutrients and sunlight. Cells in our body face the same pressures—they compete for space, nutrients, and oxygen, too.
Our question is a simple one with big implications: Can we generate specifically engineered cells that are ‘more fit’ and can eliminate less-fit cancer cells?
Until recently, that seemed impossible. In 2012, the Nobel Prize was awarded for the creation of ‘induced pluripotent cells’ (iPS cells). iPS technology allows researchers to revert cells back to stem cells and then use those stem cells to produce specialized cell types. It would be similar to taking a cake and reverting it back to flour, and then changing it to another food, like cookies.
This discovery challenged a fundamental concept of development and opened new possibilities in regenerative medicine. This lab has used the same technique that created iPS cells to engineer “induced tumor-suppressing” cells (iTS cells). Their laboratory work has shown iTS cells can effectively kill breast cancer cells, as well as prostate and pancreatic cancer cells, likely by secreting certain proteins which kill less-fit cancer cells.
These factors could potentially be developed as cancer therapies, but the concept needs to be proven. Funding this project would allow for further preclinical study and mock pilot clinical trial testing using iTS cells in animal models.
Successful completion of the proposed study will move us closer to clinical testing of this unique potential treatment option.
Elizabeth Yeh, PhD
Metastatic disease is currently incurable. We have identified a molecule, called HUNK (Hormonal Upregulated Neuassociated Kinase), that is critical for breast cancers to metastasize.
When we eliminate HUNK or block its function in pre-clinical models, the cancers don’t metastasize. This suggests that targeting HUNK may be a useful treatment strategy. Unfortunately, there are no known chemical inhibitors of HUNK. Until recently it wasn’t possible to screen drugs for activity against HUNK. We have solved that problem and have already developed a reliable test capable of screening thousands of compounds.
The goal of this proposal is to streamline the identification of a clinically relevant HUNK inhibitor by using a modified “me too” drug discovery approach. We will take FDA-approved agents already being applied to treat cancer and test them for their ability to bind to HUNK.
We will then test whether those that bind HUNK block its activity. Because the agents we want to test are already FDA approved, clinical application will be streamlined.
The major benefit of this approach is that “re-positioning” FDA approved agents will cut out the time consuming and expensive (multi-million dollar) process generally associated with traditional drug discovery.
Feng Guo, PhD and Kenneth Nephew, PhD
More than 90 percent of cancer deaths are the result of metastatic disease. Cancer cells spread through blood as circulating tumor cells (CTCs) and lodge at distant organs to form metastasis. CTCs can be detected in the blood in a test often called a “liquid biopsy”.
Primary tumors may shed millions of tumor cells into the bloodstream every day; however, only hundreds of cells or less adhere at distant tissue sites. That is to say that only a small fraction of CTCs can form metastasis.
Unfortunately, we can’t determine which of the CTCs will form metastasis and which won’t. Thus, the objective of this proposal is to develop a method that not only separates and identifies a patient’s CTCs, but also measures how well they can stick to distant tissues.
The research team hopes to determine which characteristics of a cell make it more “sticky” thereby creating a method to identify the cells more likely to form metastasis.
This proposal is a partnership between two labs. One lab specializes in acoustic and microfluidic technologies for isolating cells and measuring their stickiness. The other lab has extensive expertise in breast cancer biology and animal models of metastasis. This multidisciplinary team will test the hypothesis that the CTC stickiness is a good predictor of their ability to form metastasis.
The team aims to:
The proposed project will contribute to the development of a new method for diagnosing cancer metastasis that could save lives.
Anna Maria Storniolo, MD
There are bacteria of all types everywhere in our bodies. Bacteria were originally thought to primarily inhabit our gut and aid in digestion. They are now shown to be present in different parts of the body, including the breast, and research has determined that the type of bacteria throughout our body depends on our ethnicity.
These observations raise questions about whether variations in types of bacteria in the breast might influence breast cancer initiation, progression and metastasis.
In this pilot study, the research team will use next-generation sequencing to identify bacteria that inhabit the breasts of healthy women, women with high-risk of developing breast cancer, and women diagnosed with breast cancer.
The results will be used to map the microbiome (bacterial population) in the breasts of women of different ancestry, living in different geographic locations. Ultimately, the goal is to identify bioactive compounds produced by bacteria that protect the breast from cancer and develop those compounds to treat and/or prevent metastatic progression of breast cancer.
The team will also look at whether the same ‘bad’ bacteria are found at sites of metastatic breast cancer and whether pre-treatment with antibiotics increases response to therapy.
Anita Bellail, PhD and Chunhai Hao, MD, PhD
The researchers proposing this hunch focus their work on determining what drives metastatic breast cancer and developing new therapies to combat it. They were the first to identify that a particular protein (called SUMO1) drives cancer growth and have developed a potent inhibitor (SMIC1007) that turns off this protein.
In cell culture, SMIC1007 inhibits the growth of multiple cancers including breast, colorectal, and lung. Hunch funding will allow this team to move SMIC1007 closer to the clinic, by testing it in two different animal models.
The first model uses a breast cancer cell line that metastasizes to the lungs. In the second model, they will use tumors from actual patients growing in mice. If successful, this hunch will support a new collaborative research team in generation of preliminary data necessary for the team to apply for the Department of Defense Breast Cancer Research Program and/or NCI drug development grants.
The ultimate goal of this project is to launch clinical trials of SMIC1007 treatment of metastatic breast cancers within five years.
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 rapidly 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 negative 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 received 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 NBC patients.
The preclinical trial data to support the initiation of this trial were made possible by 100 Voices of Hope’s funded Hunch #4.
With help from your seed funding, our researchers recently received a National Cancer Institute grant to even further expand this project.
Hiroki Yokota, PhD
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:
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 treatments for preventing bone metastasis and could significantly improve the efficiency of drug delivery for breast cancer patients.
Richard Carpenter, PhD and Kenneth Nephew, PhD
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 percent to 25 percent 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 epigenetics, 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.
Better results for patients are possible through our exploration of the genetics that drive tumors, what makes tumors more susceptible to treatment, and devising therapies to defeat breast cancer while avoiding toxic side effects.
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.
Funded in memory of Carrie Glasscock West
Tao Lu, PhD and Lang Li, PhD
We hypothesize that high expression of some key proteins leads to drug resistance in metastasized breast cancer. Recently, our 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.
Milan Radovich, PhD
Dr. Radovich 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. Their hope is that this combination will provide a new “precision medicine” based drug combination for triple negative breast cancer.
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. 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.
Hiroki Yokota. PhD, and David Agarwal, MD
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.
New discoveries start with your gifts. This vital work means so much to breast cancer patients, their families, their friends, and the communities they enrich.
The investigators are studying a group of metastasis suppressor genes (MSGs) 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.
The main question this research is trying to answer is: How do cancer cells turn off MSGs? Using data from the Cancer Genome Atlas, an NCI-sponsored project including genomic data from almost a 1,000 breast cancer patients, the team will identify and analyze lncRNAs associated with metastasis.
Samy Meroueh, PhD
Dr. Meroueh’s 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.
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 re-sistant 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.
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.
The goal of this project 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.
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 investigators a picture of genes that can be targeted for therapeutics.
Hari Nakshatri, PhD
Dr. 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.
