UCLA Jonsson Comprehensive Cancer Center

UCLA Research

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.

2013 Update

Developing a Novel Epigenetics Therapy for the Treatment of Breast and Ovarian Cancers Dr. Ramin Nazarian, PhD andJohn Glaspy, UCLA’s Jonsson Comprehensive Cancer Center

Last year, NFF made a grant to Dr. John Glaspy and his team at UCLA to establish an epigenetics lab that will allow researchers at UCLA to collaborate with scientists at Johns Hopkins to develop a breakthough new epigenetics therapy for breast cancer and potentially ovarian cancer. Epigenetics is a new area of science dealing with the genetic changes that take place at the cellular level as we age. An epigenetic therapy has proven extremely effective in treating leukemia and lung cancers and doctors at both UCLA and Johns Hopkins believe that they can apply the research to breast cancer treatment and most likely ovarian cancer treatment as well.

Preliminary data generated in a collaboration between Johns Hopkins and UCLA indicate that epigenetic changes are very important in the biology of human ovarian and breast cancers, including their evolution to more aggressive and treatment-resistant pehnotypes. The researchers believe that therapies that reverse epigenetic changes (hypomethylating agents and/or histone deacetylase inhibitors) are potentially very powerful tools in the treatment of breast and ovarian cancers and believe that within 18 months from the beginning of the study, they will be able to collect enough data to begin a Phase I trial. Work will begin soon, it had been delayed due to some issues at Johns Hopkins.

NFF provided additional funding so that the researchers can finish their work without having to apply for a grant from another source. We will be given full credit for funding the lab.

Targeting the Cyclin D:cdk-4/6 Pathway- New Treatment in Phase III Trial.

Cell growth and division in normal breast cells is tightly regulated. One 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.

As part of the laboratory research efforts funded by 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 cdk-4/6 function. Their research found that blocking it with a novel agent, a drug currently named “PD 0332991″, which is 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 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 (“PD 032991”) 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 a large pharmaceutical company 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.

Targeting the Epidermal Growth Factor Family in 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.

Ovarian Cancer Research:

Identification of Ovarian Cancer Subtypes and Therapeutic Implications

Epithelial malignancies of the ovary constitute the number one killer of women with gynecologic malignancies in the U.S. today. In more than 75% of the newly identified cases, the disease has already reached an advanced state (stage III or IV) at the time of initial diagnosis. Once diagnosed, the best available treatments involve aggressive surgical procedures followed by punishing chemotherapeutic regimens. Despite these efforts, more than 85% of patients have succumbed to their disease within seven years following initial diagnosis. This is a disease in desperate need of new, innovative and more effective therapeutic strategies.

Like breast cancer, all ovarian cancers are not alike. This explains why the outcomes for standard, one-size-fits-all chemotherapy regimens vary so widely. In fact, ovarian cancers can be divided into clearly identifiable genetic sub-types, each of which requires a distinct treatment strategy. Ultimately, the ability to treat all ovarian cancer sub-types successfully depends entirely on how precisely each sub-type can be characterized and distinguished molecularly.

With support from the Noreen Fraser Foundation, UCLA scientists have undertaken research to understand the molecular alterations that may be critical in converting a normal ovarian epithelial cell into a malignant one. UCLA has successfully amassed a collection of some 41 human ovarian cancer cell lines for laboratory screening and molecular characterization. In addition, a cohort of 225 clinical ovarian tumor samples collected between1989-2005 has been molecularly dissected. Results indicate that while all of these cell lines and tissues are malignant, their molecular “fingerprints” can be grouped into a handful of specific subtypes. Each subtype reflects different identifiable cell signaling pathways causing a tumor’s growth. One such pathway is known as IGF-1. A targeted non-toxic agent that interferes with IGF-1 signaling was initially tested successfully in our cell line models in the laboratory, and the results led to the implication of alterations in an important pathway in a proportion of these cancers. As a result a clinical study is now being accrued to analyze the results of this inhibitory agent in patients whose ovarian cancers may be driven by IGF-1.

Sixty (60) patients with ovarian cancer that recurred after surgery and chemotherapy have been accrued to this trial. Each patient received the targeted non-toxic agent first to determine safety, and second to determine effectiveness. Final efficacy and toxicity analysis is now being performed. A common but mild side effect was the temporary increase of blood glucose levels. The investigational drug is safe and potential side effects are manageable in the clinic. Approximately 30% of the patients demonstrated some positive response to the treatment in the initial testing phases of this approach. This finding is very encouraging as it confirms the hypothesis that there is a subgroup of ovarian cancer patients that has an activated IGF/IGFR signaling pathway and that can potentially benefit from a treatment strategy targeting this pathway.

***** UPDATE *****

NFF Funded Breast Cancer Research at UCLA's Jonsson Comprehensive Cancer Center Leads to Phase III Trial

Background

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.

Targeting the Cyclin D:cdk-4/6 Pathway.  Cell growth and division in normal breast cells is tightly regulated.  One of the main proteins involved in theregulation 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.

As part of the laboratory research efforts funded by 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 cdk-4/6 function.  Their research found that blocking it with a novel agent, a drug currently named "PD 0332991", which is 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 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 (“PD 032991”) 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 a large pharmaceutical company dedicating $190 million 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.