The goal of the proposed research is the development of methods that would permit early intervention in the progression of breast cancer, for which the investigator plans to isolate mammary intraepithelial neoplasia (MIN) cells and determine their “trajectory” to invasive cancers. These studies will serve as a prelude to the development of improved diagnostics and stem cell-specific therapies. The core of the planning team will include a clinical pathologist, a stem cell biologist, and an expert in the molecular biology of breast cancer. Key features of the planning process will involve the establishment of collaborative commitments, workshops to facilitate team interaction, identification of proposal components, and planning of regulatory and administrative aspects of the research proposal.
This proposal is focused on a highly significant clinical problem, breast cancer, and on the important goal of facilitating early intervention in breast cancer progression. However, the reviewers’ enthusiasm was limited by the absence of sufficient preliminary evidence and base knowledge about breast cancer stem cells, and the low probability for developing clinical trials within five years.
The concept is based on the isolation, propagation, and analysis of breast cancer stem cells. The proposed target cells remain poorly characterized, and evidence for the existence of this cell population is meager. Reviewers were concerned that even if such cells could be isolated and characterized, it is unclear how early predictors of cancer progression would be identified and, moreover, how such information would lead to the development of a clinical trial.
The PI is a distinguished breast cancer pathologist. Reviewers were concerned about lack of evident experience in leading disease team-based research initiatives or clinical trials, though he/she has published extensively on breast cancer tumorigenesis.
The planning approach is clearly described and follows a reasonable and appropriate progression. A clear strength of this aspect of the proposal is the collaboration of two institutions with excellent research capabilities and resources. Individuals with appropriate expertise are identified as prospective team members. The absence of a record of prior, substantial collaborations between proposed team members diminished reviewer enthusiasm, but firming up the collaborations was a stated goal of the planning process.
The persistence of cancer stem cells has been proposed to underlie recurrence, metastases, and resistance to treatment of some or many types of cancer. The applicant Disease Team and others in the breast cancer field have shown that these cells arise in breast cancer at a very early stage, initiating the preinvasive lesions recognized as ductal carcinoma in situ (DCIS). The objectives of the disease team are to isolate, propagate, and biologically assess breast stem cells to provide improved diagnostics, devise predictive assays, and develop stem cell-specific therapies. The first goal of this planning grant is to establish milestones toward the conduct of clinical trials to prove the specificity and sensitivity of prognostic assays. The second goal of the planning phase is to investigate cell isolations and propagations for predicting response to therapies. Finally, the disease team will consider the use of cell growth and differentiation or senescence assays from the DCIS stem cells as a form of personalized medicine.
Reviewer One Comments
The key aim in this proposal is to develop methods that would permit early intervention in the progression of breast cancer by isolating mammary intraepithelial neoplasia (MIN) cells and determining their “trajectory” with respect to invasive disease. The PI states that one can grow MINs as mammospheres (equivalent to DCIS) and then characterize these cells by gene expression profiling, etc. The hypothesis is attractive, but designing and executing a trial is challenging. At present there are no guarantees that suitable predictors of malignancy can be defined in MINs in the short term. If the goal is developing trials within 5 years, it is this reviewer’s view that this proposal falls short in this regard. In addition to the upfront issues, the length of time to follow effects of therapy in this setting is very long. If one could define early predictors in DCIS/MIN, the impact on management of breast cancer therapy could be enormous. Nonetheless, as a CIRM disease target in the short term, I do not think this is of the highest priority.
The PI is a senior and respected pathologist who has contributed significantly to the breast cancer field, particularly in his role as an authority on breast cancer pathology in the mouse. Experience in leading a human disease trial team is not evident but he has assembled a disease team with suitable expertise. His background in the pathology of breast cancer fits nicely with the proposed hypothesis.
The planning approach is reasonable with assembly of the disease team, a focused workshop, followed by identification of specific proposals to put forward for development and planning.
Reviewer Two Comments
This proposal targets cancer stem cells, which currently remain poorly characterized, but share the potential for self-renewal and regeneration of entire mature tumors. The presence of these cells has been reported in breast cancer, thus the isolation and characterization of the cells represent significant and high-priority endeavors. Despite the PI’s claim for the evidence supporting the existence of these cells, the scientific evidence remains very poor, and thus does not seem mature enough at the basic level to provide a strong platform for disease approach at this point. That the approach offered in the proposal will offer a revolutionary approach to disease of breast cancer does not at this point seem justified.
The main elements of the concept are: 1) use of pre-cancer stem cell like cells for prognostic and diagnostic; and 2) to grow the stem cell like pre-cancer cells in mice and optimize the culture system. The other innovative approaches suggested by the applicant have already been shown to not yield any positive results so far, including screens for compounds that change the differentiation of a stem cell to a benign state.
The strength of the proposal overall remains the significance of the target disease and the collaboration between UCD and Burnham. The weaknesses include poor preliminary base knowledge of cancer stem cells of the breast, and the ambitious nature of the approach.
Dr. Robert Cardiff, MD. PhD is a pathologist. He has 5% effort committed to this proposal. He earned the PhD at UC Berkeley in 1968 in Zoology. The team also includes Dr. Jan Nolta, PhD, an expert in stem cell isolation and propagation. She is a cell biologist who will assist with future regulatory requirements. Another core member is Dr. Robert Oshima, PhD., Burnham Institute. He is an expert in breast cancer, cell biology, mouse stem cells and mammalian tumor biology.
This proposal combines the efforts of UCD Cancer Center, UCD stem cell program and the Burnham Institute. Six phases are proposed. Phase 1 is the commitment which involves two parts: the agreement of various investigators at UCD, as stated above and the commitment of a team of advisors, including Dr. Altrock (UCSB) and a shopping list of other local talent. Phase 2 is a workshop. Despite the claim of the PI, no extensive record of collaboration among the team members is documented. A face-to-face workshop is scheduled for August 2008, which will then focus on Phase 3. Phase 3 has a couple of subparts focused on the development of novel technology required for the project, and development of diagnostic/clinical trial designs. Phase 4 will focus on regulatory planning. Dr. Altrock has initial IRB protocol to obtain cells from women at high risk of breast cancer. Phase 5 is administrative planning under the joint leadership of the co-PIs who will oversee project assessment. Phase 6 is proposal submission