2003: Immunotherapy Focus on Brain Cancer
$150,000 - T cell Therapy
T cell therapy takes immune system cells from the patient and reprograms them through genetic engineering. The reprogrammed cells are then reintroduced into the patient's body. The expectation is that these T cells will kill only the tumor cells while leaving normal cells unharmed.
Our first Board of Governors grant provided the necessary funds for Michael Jensen, M.D. and Andrew Raubitschek, M.D., to begin the first-in-human trial of reprogrammed T cells for glioblastoma, an aggressive form of brain cancer. Both Dr. Jensen and Dr. Raubitschek are no longer at City of Hope.
Currently, the T cell trials are ongoing and show great promise in facilitating a cure for this devastating cancer.
2004/2005: Infrastructure to Support Clinical Trials
$500,000- Clinical lmmunobiology Correlative Studies Laboratory (CICSL)
$150,000 - Laboratory Specialist
2006: Research Into a Key Protein for Cancer
$150,000 - STAT3 Protein Study (Fast Track)
Hua Yu, Ph.D., the Billy and Audrey L. Wilder Professor in Tumor Immunology and associate chair of the Department of Cancer Immuno-Oncology, is co-leader of a team of researchers who found that STAT3 protein is found in almost all cells in our body. As a general rule STAT3 is dormant in normal cells. In contrast, STAT3 is constantly active in cancer cells and in the immune cells within and surrounding tumors.
Hua Yu, Ph.D., was the first to show that blocking STAT3 in tumors leads to tumor regression. Additionally, Yu and her colleagues discovered that the active STAT3 protein strengthens the tumor cells while weakening the natural defense mounted by the immune cells around a tumor. By deactivating STAT3, Yu found that not only does the tumor cell die, but the surrounding immune cells regain their ability to fight cancer cells. BOG grant enabled Dr. Yu to focus on a “fast track” process where no government funding was available. With the results she established from our “seed money” she has been able to apply for and receive numerous major grants from the National Institutes of Health and others.
Currently, Dr. Yu reports that significant progress has been made in translating CpG-STAT3siRNA to clinical trials and part of the manufacturing toxicity studies are completed. Though facing some challenges in large-scale manufacturing of the materials for human use, they have overcome the most difficult hurdles and are optimistic about moving this project forward into clinical trials. While they encountered these difficulties which they did not anticipate, her team is doing things no one has ever done before--optimizing the human version of the STAT3 protein and are now producing quality STAT3 products to be used in clinical trials for the treatment of glioma and B-cell lymphomas.
Dr. Yu and City of Hope have a patent on the technology filed and granted by the US patent office, an amazing step toward achieving their goal and ultimately helping humanity.
Dr. Yu has been recognized by major organizations and in 2014 was awarded the Humboldt Award. This prize, also known as the Humboldt Research Award, is given by the Alexander von Humboldt Foundation to internationally renowned scientists and scholars.
She and her colleagues have received several grants totaling about $6 million that are enabling the City of Hope scientists to advance the research initially supported by BOG. She is most appreciative of the BOG seed money which enabled her to prove her initial findings that was the foundation for greater achievements and incredible financial support. The importance and impact of her findings were recognized by City of Hope and they awarded her $1,000,000 to complete the clinical trials of CpG-STAT3siRNA..
2007: Clinical Research Advancement Fund
$500,000 - Fund Hiring Five Clinical Trial Physicians
The growth of the clinical trials program required an increase of doctors to treat and monitor patients in therapies being brought from the laboratory bench to the patient bedside. This grant was established to support the salary requirements for up to five doctors. These physician-researchers were specifically recruited to help design and then execute the phase 1/2 trials ready for in-human treatment. Initially three doctors were recruited in 2008 and our grant has allowed another five doctors to be recruited through 2012.
2009: Studies That Seek to Improve Care for Older Adults
$250,000 - Creating Geriatric-Specific Treatment Protocols
Arti Hurria, M.D., served as the director of the Cancer and Aging Research Program, concentrated her research on cancer in the aging population and developing more patient-friendly treatments. Our grant was to provide the funds for a study of the effects of chemotherapy in the older population.
Dr. Hurria received NIH grants totaling about $7 million and from philanthropic funding approximately $3 million including several grants from the Breast Cancer Research Foundation.
2011: Targeting the Mechanism Behind Cancer's Growth
$250,000 - Attacking the DNA That Replicates Cancer Cells
Linda Malkas, Ph.D., deputy director of basic research and professor and associate chair of the Department of Molecular and Cellular Biology, has discovered a key protein within a breast cancer cell that replicates the cell and creates a tumor mutation which continues to copy. She has identified six agents (out of more than 6 million tested) that inhibit this protein from reproducing - thereby stopping the cancer in its tracks. She is also collaborating with Hua Yu, Ph.D., our 2006 grant recipient. Dr. Malkas believes the BOG grant will give her the needed funds to bring her research from the bench to the bedside and begin the first-in-human trial of her protocol within two years.
UPDATE: Neuroblastoma is one of the most common childhood neoplasms, brain cancer. Dr. Malkas' team previously reported a novel cancer which was significantly expressed in a broad range of cancer cells, but not in nonmalignant cells. Dr. Malkas and her research team designed a molecule to test this hypothesis. Their investigation shows that this molecule selectively kills human neuroblastoma cells with very little toxicity to nonmalignant cells. They are working with pediatric oncologists to conduct preclinical testing.
A small molecule compound, AOH39 potency, shows significant promise for arresting neuroblastoma and breast cancer. David Horne, Ph.D., vice provost and associate director of Beckman Research Institute of City of Hope, has been able to chemically modify the original AOH35 potency, increasing its effectiveness by 10 times, thereby greatly increasing its ability to inhibit a cancer cell’s ability to repair damage to it and therefore it dies.
According to Dr. Malkas’ progress report dated July 2015, Attacking the DNA That Replicates Cancer Cells, they have made significant progress on their project to identify a new generation of cancer therapeutics. The funds provided by the Board of Governors has allowed them to move rapidly. Dr. Malkas has discovered that a key human cell DNA replication/repair protein is uniquely altered in cancer cells. She used this protein as a molecular target for the development of agents that specifically kills cells. The protein, proliferating cell nuclear antigen (PCNA), plays an essential role in regulating DNA synthesis and repair and is indispensable to cancer cell growth and survival. It represents an attractive molecular target to develop broad-spectrum anti-cancer agents. By targeting a cancer specific domain of PCNA, they identified a novel compound, AOH1160, which selectively kills cancer cells at below micro-molar concentrations, but causes no significant toxicity to a broad range of nonmalignant cells. They are in the process of preclinical development of this compound with a goal of bringing it to the stage of clinical evaluation in the near future. Their goal is to advance AOH1160 to the stage of clinical evaluation and meet FDA investigational new drug (IND) requirements. They will produce sufficient quantities of AOH1160 (1 kg) to meet FDA GLP/cGMP regulations to ensure that the quality of the compound used in the preclinical studies is equivalent to the quality required for conducting clinical trials. Also, they will fully assess AOH1160 physicochemical properties and use these results to design and optimize compound formulation suitable for administration to patients. They will further evaluate compound safety in 21-day chronic dosing toxicology studies which are an integral part of IND requirements and will inform selection of a safe starting dose for clinical trials. Dr. Malkas participates in various advisory committees and institutes, both private and government sponsored. She has received several millions of dollars in grants from private foundations and the National Cancer Institute, as well as government sponsored programs, including the Department of Defense Medical Research and Development Command Research Program. Currently she is principal research investigator in a pending grant of $25 million from the National Institutes of Health/Center for Translational Science Award (2016-2021) “Inland California Translational Consortium.”
2013: Merging of Eastern and Western Medicine
$100,000 - Using Natural Compounds Found in Traditional Asian Medicine
John Hosei Yim, M.D., associate professor of surgery, performs breast and endocrine surgery, and conducts research for breast and endocrine cancer treatments. Dr. Yim works with natural compounds found in traditional Asian medicine, as well as superfoods such as blueberries, mushrooms, and soy. His laboratory has discovered a compound found in a Chinese root, baicalein, which activates a protein that causes cancer cells to kill themselves and makes them more susceptible to the person's immune systems. It can also inhibit cancer cell growth in glandular tissue including breast, prostate, ovary and even colon. According to his studies, tumors can shrink in mouse models, including those that are resistant to chemotherapy. They have given baicalein both by injection and orally to mice with cancer in numerous models and have found a marked inhibition of growth of their tumors. Dr. Yim's therapy can combine with chemotherapy to shrink tumors even further, while lessening the toxicity of the chemotherapy. They discovered baicalein as a potent activator of IRF-1, which enhances the immune response against cancer cells and causes them to kill themselves (called apoptosis.)
There are already over a thousand studies published by us and others around the world on the promise of baicalein as an anti-cancer agent performed in animals and on cancer cells in culture.
His team has developed a method to synthesize pure baicalein. Not surprisingly, because the synthesized baicalein is 99.6% pure and not extracted from roots from China, this baicalein is more potent than the extracted baicalein, especially in terms of activating IRF-1. They have synthesized 100 grams already which is enough for as many animal studies as they want. However, there is no baicalein pill for patients as yet and no studies looking at how baicalein can treat patients.
Like no other institution, City of Hope will make these pills at the pharmaceutical plant on campus. They will manufacture the clinical grade baicalein pills which eventually will be given to patients being treated at City of Hope and allow for studies to confirm its safety and efficacy in tumor bearing mice, in preparation for Food and Drug Administration approval for clinical trials.
The plan is to make two kilograms of pure baicalein, enough to perform a phase I clinical trial, and make pills including the two ingredients and perhaps with one or more ingredients. They will then need FDA approval to perform the clinical trial which will probably take at least a year, and plan to start the phase I clinical trial in 2017.
Dr. Yim's team has discovered more exciting aspects of baicalein treatment. In particular, they found that baicalein increases a protein called DDIT4 that inhibits a pathway called mTOR, which is a target for many big pharmaceutical companies. We think both IRF-1 and DDIT4 can be measured in patients if we treat them with baicalein.
Dr. Yim credits the Board of Governors' ongoing support for achieving his results in an accelerated period of time. There are many opportunities in the future, such as studying the combination of baicalein with other anti-cancer therapies to cure cancer without hurting the patient; evaluating the chemopreventive effect of baicalein to see if it can prevent recurrences or even cancer from ever happening, and seeing how inhibition of mTOR by baicalein impacts on aging. He hopes to continue to work together to see these opportunities become reality.
In addition to publishing numerous studies in prestigious journals his team has received funding from major foundations including the Panda Charitable Foundation and the Oxnard Foundation.
2013: The Smart Bomb Approach to Curing HIV/AIDS
$100,000 - BioRad QX100 Droplet Digital PCR Instrument
John Rossi, Ph.D., Lidow Family Research Chair and professor of the Department of Molecular and Cellular Biology, and John C. Burnett, Ph.D., assistant research professor in the same department will be using this instrument to measure the levels of cancer markers and to test new therapeutics which may reduce the levels of cancer cells.
With the help of this highly precise measuring device, that gives exponential amplification of nucleic acids using their new gene editing technology, CRISPR, they will target HIV genes in infected cells. The doctors have engineered biological molecules to deliver the therapeutics only to the intended cells and devised methods to target only the HIV genes without affecting the human genes. This greatly reduces toxicity. These strategies mark a highly specific and potent approach for eradicating HIV.
Importantly, CRISPR technology will also be applicable for many types of cancers and other genetic diseases. It will also be used to develop new anti-cancer agents currently under investigation for pancreatic cancer, B-cell lymphoma and T cell leukemia.
According to Dr. Burnett, to his knowledge, no one has ever used this instrument to discover these new agents and he is preparing a patent application for this purpose making this instrument the focal point of a breakthrough technology.
Their findings will confirm that the agents can eradicate cancer and HIV in animal models. These important initial experiments will enable City of Hope to secure federal funding and prepare for the most critical step, human clinical trials with new therapeutics.
Since then, they have made tremendous strides in cancer and HIV research, in large part due to the technology of ddPCR. While this technology is very sophisticated, the practical implications are quite simple. Briefly, 5,000 tiny droplets will fit into a single teardrop for testing. Equipped with powerful lasers and detection sensors, the instrument is capable of measuring the amount of DNA in each tiny droplet. Thus, they can now measure DNA at a level far more sensitive than before.
One of the major applications with this instrument is the detection of extremely low levels of DNA from HIV-infected cells. In an effort to cure HIV, they are developing new strategies to eradicate the virus knowing that their efforts can be accurately tested and optimized.
Their new approaches to cure HIV have led to new grant funding, in part because of this technology. In March of 2014, Dr. Burnett was awarded a $200,000 two-year grant from the California HIV/AIDS Research Program (CHRP) for a new project titled “RNA-guided genome engineering for HIV resistance.” Also in 2014, Dr. Rossi received a five-year grant totaling more than $2.9 million from the National Institutes of Health for a project titled “Enhancing the Intracellular Functioning of anti-HIV RNAs.” These two projects will lead to developing new therapeutics that will eliminate HIV. They are preparing for a new clinical trial at City of Hope that would implement some of the new strategies they have developed to eradicate HIV.
In addition to HIV, they are also making important progress in cancer research in collaboration with City of Hope physicians.
2014 Activation of the Immune Response to Fight Cancer: The "PAC-MAN" Strategy.
$200,000: Develop and deliver therapeutic small molecule to cells capable of blocking cancer growth
Daniela Castanotto, Ph.D., research professor, Department of Medical Oncology & Experimental Therapeutics Research, and her research team are working on creatinga small RNA or DNA molecule that can identify abnormal cells or HIV-infected cells and deliver a “therapeutic cargo” directly and only to those cells.
The first part of their project was to screen a large library of compounds in an attempt to Identify a drug able to improve delivery of therapeutic molecules inside the cancer mass. Penetration into the cancer mass is one of the major obstacles to all cancer therapies. Among those, they identified one which is especially effective. During the laboratory tests for different types of cancer cells, they observed that this particular drug has an added property affecting prostate cancer cells.
Astonishingly, their newly identified drug can completely eliminate the cancer cells, at least in cultured cells and laboratory tests. This serendipitous discovery allows the implementation of a new strategy, which relies on the ability of this drug to improve the delivery of their therapeutic molecule which will stimulate the immune-system.
Currently they are exploring the mechanistic details by which this compound exerts its functions and are also investigating if the amount (and thus the toxicity) of chemotherapy agents used in current therapies can be reduced when combined with their drug.
While gaining a better understanding of the drug's potential own toxicity and its mechanism(s) of action, they are preparing to submit a mouse protocol to the appropriate COH committees for approval. The goal is to create a prostate cancer mouse model with cells that are resistant to the current hormonal therapies and explore the effect of their newly identified compound. They predict that this protocol will be finalized and approved within the next six months at which point they will be ready to begin the mouse studies. If the laboratory results will be confirmed in the mouse model and their treatment will show no or tolerable toxicity, they will have enough evidence to propose this drug for a Phase-1 human clinical trial.
Dr. Castanotto appreciates the BOG's financial support which has been crucial to this research. Without it they could not have carried the project this far and obtained these remarkable and very exciting results.
2015 Next Generation Drug Discovery--new technology to radically accelerate drug discovery
$200,000: Revolutionize how drugs are discovered and how they are delivered.
Jacob Berlin Ph.D., assistant professor in the Department of Molecular Medicine, Beckman Research Institute of City of Hope, and his team has just completed the first prototype of a system that will revolutionize the discovery of new drugs to fight cancer. They are developing a method to place 1 billion different molecules on a microscope slide sized chip using nanotechnology, the science of extremely small things. These chips will then be used to identify which molecules are good potential drugs for proteins that other researchers at City of Hope have identified as promising new areas for treating cancer. This will revolutionize and accelerate how drugs are discovered and how they are delivered.
It usually takes all year to test about a million compounds at great expense. Their system will test inexpensively billions of compounds in an afternoon. This will result in his lab’s ability to evaluate more potential drugs in one day than the pharmaceutical industry has ever tested.
Dr. Berlin is grateful to the Board of Governors of the City Of Hope for funding this epic challenge and being the first “investors” in making this happen. This will allow his team to accelerate this project, possibly reducing the time to identify a promising molecule by 1-2 years, and enable them to search for molecules to treat additional diseases, including resistant breast cancer, HIV and leukemia.
More detailed information on any of the above research projects is available by calling 626-218-6375.
The following doctors have all benefited from the Board of Governors grants toward their research. Their area of expertise covers cancer, immunotherapeutics, tumor immunology, surgery, oncology, hematology, neurological spine, hematopoietic cell transplantation and molecular/cellular biology:
Saro Armenian, D.O, M.P.H., Jacob Berlin, Ph.D., John C Burnett, Ph.D., Daniela Castanotto, Ph.D., Robert Figlin, M.D., (no longer at City of Hope), Stephen Forman, M.D., Julio Garcia-Aguilar, M.D., Ph.D., Ernest S. Han, M.D., Ph.D., Arti Hurria, M.D., Ruhal Jandial, M.D., Ph.D., Michael Jensen, M.D. (no longer at City o.f Hope), Michael Kalos, Ph.D. (no longer at City of Hope), Theodore G. Krontiris, M.D., Laura Kruper, M.D., Linda Malkas, Ph.D., Renee Penn, M.D., Andrew Raubitschek, M.D., (no longer at City of Hope), John Rossi, Ph.D., Timothy W. Synold, Ph.D., John Hosei Yim, M.D., and Hua Yu, Ph.D.