UCLA Jonsson Comprehensive Cancer Center received several grants from the Noreen Fraser Foundation to support research endeavors in the areas of breast and ovarian cancer research being overseen by Drs. Dennis Slamon and John Glaspy. The research funded includes preclinical work that led to the discovery of a new targeted treatment currently in a Phase III trial. An outline of all NFF funded research at UCLA is provided below.
UCLA Breast Cancer Research
We now appreciate that breast cancer is not one disease but many distinct diseases and that the only thing that all breast cancers share in common is the organ in which they arise. Consequently, breast cancer is now classified, based on gene expression patterns, into several different subtypes. These include the hormone receptor positive (ER+) groups, HER2-positive, basal-like, and normal-like, although there can be some overlap in characteristics among the subtypes. Importantly, each of these subtypes have distinct clinical outcomes and prognosis.
Approximately two thirds of breast cancers are estrogen receptor positive (ER+). Modification of estrogen activity or synthesis represents the treatment of choice for these types of cancers. There are several estrogen directed therapies available including Tamoxifen, aromatase inhibitors and direct estrogen receptor down -regulators such as Fulvestrant (Faslodex).The UCLA Translational Oncology Program has been focusing on other molecular targeted agents in the treatment of ER+ breast cancer that will provide an alternative to chemotherapy when ER+ breast cancers are inherently resistant to or develop a resistance to anti-estrogen agents.
The UCLA Translational Oncology Program has been focusing on other molecular targeted agents in the treatment of this disease.
Targeting the Cyclin D:cdk-4/6 Pathway- New Treatment in Phase III Trial.
The UCLA Translational Oncology Program is actively engaged in identifying new molecular targeted agents in the treatment of ER+ breast cancer once it acquires resistance to existing anti-estrogen agents. Their work has met with success in the development of a CDK4/6 inhibitor.
Cell growth and division in normal breast cells is tightly regulated. One (or two?) of the main proteins involved in the regulation is the cyclin D kinases 4 and 6. These proteins interact with other proteins (Cyclin D and RB) to tell a cell when to grow and when not to grow. In cancer cells, this pathway is often dysregulated allowing for uncontrolled tumor growth. UCLA researchers have evaluated investigational drugs that block cdk-4/6 function with the goal that by inhibiting this function in cancer cells, they can restrict their growth.
With funding from the Noreen Fraser Foundation, UCLA scientists screened its panel of human breast cancer cell lines and found that ER+ breast cancer cells seem to be particularly dependent on CDK4/6 function. Their research found that blocking it with a novel agent, a drug currently named “PD 0332991″, a selective inhibitor of cdk-4/6, researchers saw that ER+ breast cancer cell lines stopped growing. In addition, when taken in combination with estrogen receptor targeted drugs like Tamoxifen, the result was even greater.
The results were brought to the clinic in Phase I and Phase II clinical trials of PD0332991 (“palbociclib”) for women with advanced ER+ breast cancer. The early results from these clinical studies was astounding. The women who received the combination of the new drug, palbociclib, and an estrogen receptor targeting agent had a 64% improvement in the time to their disease progression and no significant side effects.
The impact was greater than any other therapeutic drug tested in this group of women to date. Because of the tremendous success of the research, a Phase III, randomized, multi-national, registrational trial is now being planned, with Pfizer dedicating hundreds of millions of dollars to further the study. We are extremely excited about these initial results that have been directly translated out of some of the work conducted with our support. Eli Lilly has also developed a CDK4/6 inhibitor called abemaciclib.
We are extremely excited about these initial results that have been directly translated out of some of the work conducted with our support.
Targeting the EGFR Family in Hormone Positive Breast Cancer
An additional approach that has been evaluated pre-clinically that is now moving into clinical testing is inhibition of the HER pathway in ER+ disease. As mentioned above, most breast cancers are dependent on estrogen (hormones) for their growth. In the cases where hormones and/or their receptors are important, other proteins (peptide growth factors) seem less important. Conversely, where peptide growth factors/receptors are important (like HER2 amplification) estrogen and estrogen-like steroid hormones seem less important. There is now reason to believe that some of the evolution of breast cancers in individual patients to resistant mechanisms for estrogen directed therapies is dependent on the peptide growth factors/receptors (rather than steroid hormones like estrogen).
Work done in the UCLA laboratory and as well as work done by UCLA analyzing previous clinical trials has identified a sub-group of ER+ cancers that may respond to blockade of the epidermal growth factor receptor (EGFR) family of proteins.
With funding from NFF, UCLA is now testing this hypothesis in a clinical trial for women with ER+ breast cancer that are randomized to letrozole alone or letrozole with a potent inhibitor of the EGFR family called afatinib. In this study, UCLA scientists are not evaluating all patients with ER+ disease. Instead they are testing a subset of ER+ patients that they believe are not initially dependent on hormones despite the fact that they do have hormone receptors (albeit low levels) in their tumors. This group constitutes women whose breast cancers may have inherent (de novo) resistance to hormonal therapy in their cancers at the time of initial diagnosis rather than acquired resistance.
The Use of New/Novel Models of ER+ Breast Cancers for in vivo testing of Innovative Therapeutic Approaches to this Disease Subtype
In collaboration with Dr. Alana Welm of the University of Utah’s Huntsman Cancer Center, UCLA is testing a new and exciting series of models of ER+ human breast cancers. To date, most in vivo models that have been used for pre-clinical testing have involved cell line xenografts. Although valuable information has been obtained using these models in the past, there are challenges they present. The most notable is that the cell lines from which they are derived are frequently years or even decades from the original cancer in the patient. As a result, these cell lines have been carried in tissue culture for prolonged periods of time and genetic alterations can and do occur while in culture. Many of these alterations may have no relationship to the original tumors from which the cell lines were derived. Dr. Welm has overcome this shortcoming by developing techniques to transplant actual human breast cancers directly out of the patients in which they have occurred into experimental mice. In doing this, she has introduced new models that are much closer to the patient’s original cancer (biologically and genetically) than we have ever had before. Through the collaboration supported by the Noreen Fraser Foundation, researchers at UCLA have been able to obtain these models for ER+ breast cancer for the purpose of testing new therapeutic approaches to this disease subtype. In addition, given their proximity to the original cancer, the models represent a renewable source of material for molecular genetic/pathway studies that should help UCLA researchers determine what pathways may be critical in the development of resistance to hormonal (or other) blockade in ER+ breast cancers.
Implantation with Radioactive Seeds During Time of Initial Breast Cancer Surgery (University of Alberta, Canada)
The standard of care following the diagnosis of an early stage breast cancer is lumpectomy followed by radiation. Standard radiation treatment requires the patient to receive treatment in a hospital setting 5-7 days a week for up to 12 weeks following surgery. Radiation options have expanded to include intra-operative radiation therapy more recently. This study seeks to expand options further with the implanting of permanent radioactive seeds in the breast during the initial surgery at the site of tumor removal. The radioactive seeds will release the amount of radiation needed to treat the area thereby allowing women to avoid having to go to the hospital day after day for their treatment. Convenience is not a trivial matter in this instance. Many women who live too far from a medical center to receive radiations on a daily basis as required opt for a mastectomy instead of breast conserving therapy
Researchers believe that the new therapy may lead to fewer side effects because women receive less radiation and it is concentrated in the specific area requiring treatment as opposed to the whole breast. They also seek to determine if the new therapy leads to better cosmetic results. Full breast radiation can cause pain and redness and permanently harden the breast. The procedure, requiring the implant of the seeds while the patient is already under anesthesia will be less painful and certainly much less time consuming than the current standard of care.
Epigenetics Research at UCLA
The Noreen Fraser Foundation is funding an epigenetics lab at UCLA (in collaboration with researchers at Johns Hopkins) to test a new cancer drug in breast cancer that works by reversing epigenetic changes in cancer cells. The new type of treatment may be effective in the treatment of ovarian cancers as well.
The DNA of human cells contains approximately 30,000 protein-encoding genes. Which genes are active in an individual cell, for instance, in the heart or the kidney, determines the appearance, behavior and function of the cells in each organ; control of gene expression therefore allows for organ specialization, growth and replacement of tissues and wound repair and is central to multicellular life. Human cancer cells differ from their normal counterparts in which genes they express; this difference in gene expression is the essence of cancer.
Much more recently, scientists have recognized that genetic mutations are not the whole cancer story. It turns out that changes in gene expression in a cell can be caused by mechanisms other than hereditary or acquired mutations. These changes are called “epigenetic” changes and occur normally as we age/
There are two main mechanisms for epigenetic change: 1) addition of simple single carbon methyl groups to the DNA molecule, called “methylation” and 2) simple chemical changes in the protective proteins (“histones”) that coat DNA and help to regulate folding of delicate chromosomes, called “histone modification.” It is now clear that DNA methylation and histone modification are especially prevalent in human cancer cells.
Targeting epigenetic changes is well established for the treatment of myelodysplastic syndrome (MDS), a previously untreatable early form of leukemia -- that can result from treatment with radiation and chemotherapy -- a diagnosis experienced by Robin Roberts and which took the life of writer Susan Sontag.
It is now becoming clear that epigenetic events may play a major role both in carcinogenesis and conferring resistance to rationally targeted cancer therapies. The good news is, unlike mutations in DNA, epigenetic changes can be reversed.
Dr. Ramin Nazarian, Ph.D will supervise the laboratory work funded by NFF and will collaborate with Dr. John Glaspy to develop sufficient pre-clinical data to justify a much larger grant application aimed at supporting the initiation of a phase I clinical trial within 18 months.
UCLA and Johns Hopkins generated preliminary data that showed epigenetic changes are very important in the biology of human ovarian and breast cancers, specifically, including their evolution to more aggressive and treatment- resistant phenotypes. Researchers believe that therapies that reverse epigenetic changes (hypomethylating agents and/or histone deacetylase inhibitors (HDAC inhibitors) are potentially very powerful tools in the treatment of breast and ovarian cancers.
There are two classes of drugs that require study. The “hypomethylating” agents, of which azacytidine will be the agent of choice, and the HDAC inhibitors, of which entinostat will be the most promising agent. For ER+ breast cancers, the researchers will test the entire bank of cell lines for:
1) effects of estrogen deprivation alone on growth inhibition (control) 2) comparative effects of pre-treatment with azacytidine (Vidaza) alone on the growth inhibition in these cell lines 3) comparative effects of pre-treatment with entinostat alone on the growth inhibition in these cell lines 4) comparative effects of azacytidine (Vidaza) combined with entinostat on the growth inhibition in these cell lines
Although estrogen receptor expressing (ER+) human breast cancer is often initially controllable with estrogen blocking therapy, these tumors usually become resistant to this treatment and develop the ability to grow in the absence of estrogen. Despite the availability of multiple hormone therapies, more women die from ER+ breast cancer than any other subtype of this disease because so many women have it.
The researchers hypothesize that pre-treatment with azacytidine will make ER+ breast cancer more dependent on estrogen, by reversing the epigenetic changes that decrease estrogen sensitivity over time. The preclinical experiments may support this hypothesis and if they do, can also define the duration of exposure necessary to have this effect. It is possible that entinostat plus azacytidine will be more effective in these preclinical models. When the scientists have these data in hand, they will be in a position to launch a proof of concept clinical trial in women with ER+ metastatic breast cancer that have had progression on estrogen-directed therapy. This trial would utilize either azacytidine alone or the combination of entinostat and azacytidine, depending upon our data.
University of Chicago – Developing Biomarkers for Early Detection of Aggressive Breast Cancer
The Noreen Fraser Foundation’s awarded its first translational research grant ( why is this called the first?) to Dr. Olufunmilayo F. (Funmi) Olopade, M.B., FACP, Professor, Department of Medicine and Director for the Center for Clinical Cancer Genetics at the University of Chicago Cancer Research Center.
NFF’s grant allows Dr. Olopade to launch a first of its kind genome-wide study to find genes that may be responsible for an aggressive form of breast cancer known as estrogen receptor (ER) negative breast cancer. ER negative breast cancer is highly aggressive, resistant to treatment and presents with a poor prognosis and yet it is a breast cancer subtype that has been understudied. Notably, ER negative breast cancer disproportionately affects women under the age of 40 and women of African and African American ancestry.
Developing Biomarkers for Early-Detection of Aggressive Breast Cancer, Dr. Funmi Olopade, Unviersity of Chicago
Dr. Olopade’s laboratory has been at the forefront of breast cancer research and is a previous recipient of a Noreen Fraser Foundation grant.
With the funding provided in 2013, Dr. Olopade’s team will leverage work already done in the lab to develop novel biomarkers for the early detection of aggressive breast cancer in at risk women.
Globally, early onset breast cancer (breast cancer in younger women) is poorly understood. Younger women diagnosed with breast cancer are more likely than older women to be diagnosed with ER negative breast cancer, a subtype of the disease that is highly aggressive, resistant to treatment, and associated with poor prognosis.
Currently, there is no defined strategy for detecting aggressive breast cancer early. Screening guidelines do not recommend mammography for young women. For women of age for screening, aggressive breast cancers develop quickly, often presenting between mammograms. This is referred to as an “interval” cancer, a cancer detected within 12 months of a normal mammogram, in women undergoing yearly mammograms.
Dr. Olopade has shown for the first time that breast cancer in BRCA1/2 mutation carriers and other breast cancer gene carriers under the age 40 can be downstaged through surveillance with mammography (MMG) and bi-annual magnetic resonance imaging (MRI). Dr. Olopade’s team evaluated the efficacy of semi annual MRI in high-risk women against conventional wisdom of yearly MRI. The work supports MRI screening every 6 months as an effective screening strategy and a viable alternative to prophylactic mastectomy in women with inherited mutations in cancer susceptibility genes. These findings were presented to great acclaim at ASCO in June 2013.
As part of her work on the MRI trial, Dr. Olopade’s team collected breast tumors and blood samples of aggressive forms of breast cancer and -- with funding from the Noreen Fraser Foundation – will (or has) test them with cutting edge genomic technology to determine if there are susceptibility genes in early onset aggressive breast cancer and investigate their potential role for early detection and prevention (who is using this word???) of breast cancer.
While risk factors and therapy for ER positive breast cancer have been clearly identified, little is understood about ER negative breast cancer, including its genetic and environmental risk factors, appropriate screening methods, and effective treatments. For reasons that remain unknown, women with BRCA1 mutations who develop breast cancer are more likely to be diagnosed with the ER negative subtype. However, there may be other genes and environmental factors (e.g., diet, physical activity, hormone replacement therapy, exposure to toxins) that interact to promote ER negative breast cancer development in young women, especially those with a strong family history of the disease. Dr. Olopade and her team are looking to fill in these knowledge gaps by taking a whole-genome approach to studying the development of early-onset ER negative breast cancer.
Using tissue and blood samples from the Breast Cancer Family Registry and the University of Chicago, Dr. Olopade and her team will use the latest genomic technologies to perform whole genome scans that can be shared with the larger cancer research community to identify and validate susceptibility genes in early onset ER negative breast cancer and investigate gene-gene interactions. The study also aims to identify novel associations between genetic mutations, other than those of BRCA1/2, that modify the risk of estrogen receptor (ER) negative breast cancer. Ultimately, it is Dr. Olopade’s hope that this research contributes to a larger effort to reduce cancer mortality and improve clinical outcomes for all women with breast cancer, especially those who are from high-risk families and were diagnosed at a young age.
Enhanced screening, adjuvant therapy and targeted therapies developed over the past several decades have improved the outlook for many cancer patients, yet breast cancer is still the leading cause of cancer death for women under the age of 40. While great progress has been made regarding the biology and successful treatment of estrogen receptor (ER) positive breast cancer, very little is known about ER negative breast cancer. We need bold, new approaches to determine the genetic and environmental risk factors, appropriate screening, and effective treatments necessary to make a greater impact on this increasingly common subset of breast cancer.
New Breast Cancer Models
NFF’s 2012 grant to Dr. Alana Welm and her team at the University of Utah Huntsman Cancer Institute, aims to create better models that more fully represent molecular diversity (beyond ER, PR and HER2) for discovery of new more targeted cancer treatments and to test new inhibitors of the Ron receptor tyrosine kinase for efficacy against breast tumor growth and metastasis.
Dr. Welm has successfully developed a collection of unique, one-of-a-kind new models for breast tumor growth and metastasis, in the form of transplantable tumors derived directly from individuals undergoing treatment for breast cancer. These breast tumor grafts retain critical characteristics of the original tumor specimens and recapitulate several important features that make them more effective preclinical testing of novel treatment strategies than any model before them.
These new “tumor grafts” have already proven to be better tools than traditional grafts.
First, the current bank of grafts, while limited in number, encompasses the major clinical and molecular subtypes of breast cancer. This will be an important feature for development and testing of subtype specific therapies.
Second, the grafts maintain critical features of the original tumors from which they were derived including histopathology, clinical markers, gene expression profiles, DNA copy number variations, and estrogen dependence and/or responsiveness.
Third, many of these grafts spontaneously metastasize to many of the same organs that were affected in the patients from which they were derived and, as such, give us important and novel models in which to test the treatment of metastatic disease.
Fourth, initial data indicate that tumor engraftment using this system is a prognostic factor for survival time, even in newly diagnosed breast cancer patients without known metastatic disease.
Together, the data reinforce the notion that these novel breast cancer explants more accurately represent the cancers from which they are derived than established cell lines or engineered transgenic animals and makes them ideal models for further study and characterization and, most importantly, for new drug testing and development.
NFF’s funding will allow Dr. Welm to increase the sample size of each of the known subtypes in order to capture the diversity of human breast cancers. The newly derived tumor grafts, along with those already established, will be utilized in both the University of Utah and UCLA laboratories for testing exciting new therapeutic approaches, and they will work together, in synergy, to further characterize these tumors and their corresponding drug responses.
Test new inhibitors of the Ron receptor tyrosine kinase for therapeutic efficacy against breast tumor growth and metastasis
Dr. Welm’s team has identified a key pathway that is critical for metastasis in transgenic models of breast cancer: the Ron receptor tyrosine kinase pathway. Like HER2, Ron is a growth factor receptor that promotes tumor growth and metastasis and is unregulated in a large proportion of human breast cancers. Dr. Welm will test novel Ron inhibitors in the patient-derived tumor graft models to definitively determine whether blockade of Ron signaling is a viable new option that is ready to be tested in breast cancer patients.
Dr. Welm’s team has discovered that Ron kinase inhibitors are effective in her models to prevent metastasis of mammary tumors. These inhibitors also prevent bone destruction due to bone metastasis. Ron inhibitors must now be tested in the best models possible, before they can move to clinical trials. The data suggest that Ron inhibitors work by simultaneously blocking both tumor progression/metastasis, and by activating the body’s own immune response against the tumor cells. This two-headed approach may be more effective against breast cancer than other single agents. Dr. Welm’s team will test Ron inhibitors against all breast cancer subtypes using our tumor graft models and we will be able to measure effects of the drugs on metastasis as well as on primary tumors.
Ron inhibitors, are exciting new drugs that may block metastasis of breast cancer, decrease bone destruction, and increase the anti-tumor immune response. Dr. Welm will work to validate these inhibitors in her state-of-the-art tumor graft models as a step toward clinical development for improved breast cancer therapy. Need to indicate status of this work now.