100 Voices of Hope Hunch History

Hari Nakshatri, PhD, and Kathy Miller, MD

Normal cells become cancerous through a process called tumorigenesis. During tumorigenesis, normal cells fail to die when instructed to die and continue to grow. The ability of cells to grow continuously by failing to die is called “immortalization.” Immortalization is the first step in tumorigenesis.

Little is known about what happens at the beginning of this “immortalization” process. In our preliminary studies, we found that pathways FACT and its interacting partner TONSL are increased in immortalized (but not yet cancerous) cells compared to normal cells.

This finding tells us that the TONSL-FACT complex is increased during the first step in tumorigenesis. TONSL is increased in 22% of breast cancers. This increase in TONSL is caused by an increase in the number of copies of its gene through a process called gene amplification. Patients with tumors with higher TONSL levels have a poor prognosis (outcome) and respond poorly to endocrine therapies.

Fortunately, there is a class of drugs called curaxins that can attack and inhibit the function of FACT. One curaxin called CBL0137, has successfully completed early studies in patients with cancer with limited side effects. CBL0137 inhibited the growth of only those breast cancer cells with higher levels of TONSL in laboratory animals.

We propose a two-stage phase II trial of CBL0137 monotherapy in patients with 8q24.3 amplified metastatic breast cancer. We will screen patients for TONSL amplification using Nanostring technology platform (test already developed and validated), allowing patients to be screened while they are receiving other therapies.

Screening will be conducted on archived tissue from the patient’s primary tumor or a prior metastatic biopsy; patients will NOT undergo fresh tumor biopsy solely for the purpose of screening for this trial. The trial will enroll 15 patients in the first group. If none benefit from CBL0137 treatment, the trial will end. If at least 1 patent benefits, the trial will enroll an additional 10 patients.

Tumor and blood samples before and after treatment will help us discover why (oy why not) and how TONSL inhibition impacts tumor growth.

Hari Nakshatri, PhD

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.

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.

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:

  1. Build an acoustofluidic system to isolate and profile the stickiness of CTCs; and
  2. Validate this system using breast cancer patient blood samples and animal models.

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.

Tarah Ballinger, MD

The majority of breast cancer deaths result from estrogen receptor (ER) positive, metastatic breast cancer (MBC), despite targeted therapies and treatment advances. Acknowledging that treatment affects a whole person rather than just a tumor, researchers have tried to determine how a woman’s body composition might contribute to her response to treatment.

These investigations have been limited, as weight-based measures alone do not tell the full story about a woman’s body, and women with the same weight or BMI can have very different amounts of muscle or fat.

This research team has a hunch that the amount of muscle in a woman’s body contributes to treatment outcome. Muscle is a large, active organ that influences the physical function, quality of life, metabolism, and inflammatory profile in the body. However, muscle has been understudied in women with MBC, and its impact has never been evaluated in those with ER positive metastatic disease.

To investigate this question, these researchers hope to analyze CT scans of women with ER positive MBC receiving aromatase inhibitors (the most commonly prescribed drug in breast cancer) to uncover any correlations between body composition and important treatment outcomes, including survival, quality of life, pain, and fatigue.

Results will help clinicians optimize drug dosing and potentially explain why effective drugs stop working for some patients. The long-term goal of this project is to provide recommendations for interventions that could positively impact treatment outcomes for women with ER positive metastatic breast cancer, such as state-of-the-art personalized resistance training programs and innovative non-exertional approaches to muscle development.

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:

  • 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 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.

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