Disease Team Planning
Anti cancer stem cell (anti-CSC) disease team planning is proposed to evaluate existing knowledge, identify and explore the gaps and necessary R&D steps needed to plan focused development of anti-CSC therapeutics from “bench” to clinic. CSC represent a small population of cells within a tumor, that is central to tumor development, drives growth and metastasis, and has the phenotypic properties of stem cells. Current therapies are able to eradicate rapidly dividing tumor cells in some cases, but these treatments frequently fail to eradicate CSC, resulting in tumor recurrence. CSCs are few in number, estimated at between 0.1%-5% depending on tumor type and stage of development, appear to be largely quiescent, and are enriched for the ATP binding cassette (ABC) drug resistant genes. Evidence for the presence of CSC has been found for a number of tumor sites, including brain, breast, colon and leukemia. CSC are self-renewing, able to give rise to a xenograft tumor from a single cell, and able to recapitulate all cell types in the resultant tumor. Interaction of CSC with their microenvironment (niche), including their degree of dependence on the stem cell niche, supports cancer development. The stem cell niche in adult somatic tissues plays an essential role in preventing tumorigenesis by balancing proliferation-inhibiting and proliferation-promoting signals controlling homeostatic regulation of stem cell maintenance versus tissue regeneration. It has been suggested that apparent loss of dependence of stem cells on this balanced niche induced control of stem cell proliferation, plays key roles in the development of cancer stem cells. This disease team planning will organize an interdisciplinary approach focused on the CSC drug screening assay and the classes of anti-CSC compounds identified to date exploring the remaining technological gaps. The proposed disease team will generate a research plan for advancement of our unique classes of anti-CSC based therapeutics towards the clinic, meeting CIRM’s primary goal for this initiative. The CSC screening assay identifying anti-CSC classes of compound structures is the appropriate platform for development of efficacious anti-CSC agents. These agents may, by virtue of their ability to specifically interfere with the coordinated signal transduction pathways of “self-renewal”, eradicate CSC and thereby increase the efficacy of current anticancer therapies.
Statement of Benefit to California:
In the United States and California, cancer remains the second leading cause of death after heart disease (559,650 deaths expected in US this year, source: CDC). Current anti cancer therapies are able to eradicate rapidly dividing tumor cells in some cases, but these treatments frequently fail to eradicate Cancer Stem Cells (CSC), resulting in tumor recurrence. CSC represent a small population of cells within a tumor, that is central to tumor development, drives growth and metastasis, and has some properties similar to that of normal stem cells. An anti cancer stem cell (anti-CSC) disease team planning is proposed to evaluate existing knowledge and identify and explore the gaps and necessary R&D steps needed to plan focused development of anti-CSC therapeutics from “bench” to clinic. This class of therapeutics could, by virtue of their ability to specifically interfere with the coordinated signal transduction pathways of “self-renewal”, eradicate CSC and thereby increase the efficacy of current anticancer therapies. Potential modalities for the treatment of CSC may include use of minimally toxic agents applied topically or systemically, whether individually or in combination with current anticancer drugs in the clinic. The proposed disease team will generate a research plan for advancement of our unique classes of anti-CSC based therapeutics towards the clinic meeting CIRM’s primary goal for this initiative and benefiting California.
Executive Summary The proposal is focused on the development of an anti- cancer stem cell (CSC) therapy. The plan rests on a CSC microenvironment culture assay that has been developed by the Principal Investigator’s (PI’s) organization. The core of the planning team will include scientists from the PI’s organization and external collaborators from institutions from US and abroad. Key features of the planning process will be to identify necessary research and development milestones and timelines needed to plan focused development of a CSC-therapeutics. The concept of targeting CSCs is alluring, though the evidence that current chemotherapy is ineffective because it fails selectively to kill CSCs is lacking from clinical data. The reviewers also found merit in the design of the experimental approach outlined in the proposal that is based on the notion that CSCs, like their normal counterparts, are regulated by interactions with their microenvironment. However, the reviewers’ enthusiasm was limited by the immaturity of this screening assay concept for translation to the clinic within the time period defined in the RFA. The reviewers noted that there is insufficient preliminary data and base knowledge about the composition of CSC niches in normal and tumor tissues which poses a significant constraint in the capacity to translate this niche-based screening technology broadly to CSC from diverse tissues. Moreover, as CSCs typically represent a very small percentage of cells in a tumor, it will be necessary to have ways to isolate and have a supply of such cells in order to do relevant screens to target the cells. These points are particularly relevant as the application provides no indication as to which tumor cell types will be targeted by this screening approach, although a prototype assay for a particular disease is noted. Reviewers were also concerned about the lack of details on the planning process and logistics of working with collaborators in different cities and countries. The role/contribution of the individual collaborators is also not precisely defined although many will participate in small molecule screens, structure based design and medicinal chemistry approaches. In summary the panel did not recommend this application for funding because of the limited evidence on the scientific approach and the lack of detail on the planning process. Reviewer Synopsis The PI proposes to develop anti-cancer stem cell (CSC) therapy. In this proposal he/she proposes screening for new agents that kill CSCs in the setting of acute myeloid leukemia (AML). The plan rests on a microenvironment niche culture assay that has been developed by the company. First he/she will screen for compounds and then structure activity studies, medicinal chemistry, target validation, and preclinical studies will be carried out. Reviewer one Comments Concept: The concept of targeting CSCs for acute myeloid leukemia (AML) is alluring, though the evidence that current chemotherapy fails because it fails selectively to kill CSCs is lacking from clinical data. Most evidence to date suggests that CSCs in AML may be infrequent, on the order of <<1% of cells. Therefore, it will be necessary to have ways to isolate such cells in order to do relevant screens to target these cells. The field of CSCs in AML is maturing rapidly. Therefore, this is an attractive disease target. If novel and effective CSC therapies were developed for AML it would be a significant advance as the long term survival of AML patients is < 50% in adults. Principal Investigator: The PI is CEO of the DNAmicroarray Inc. He received his PhD at UCSB and then was a postdoctoral fellow at the Scripps Research Institute. He was founder of the company in 1997. He has a publication record largely in culture methods for cancer and stem cells. Planning Approach: The planning process will include a multidisciplinary team from DNAmicroarray Inc and other institutions, largely similar companies. It is difficult to assess the cohesion of this group at the present time. There is no mention of the number of patients available to this group (two clinical team members are listed, one in pediatrics, the other in medicine and pediatrics). It will be important to have a better grasp of the number of patients, the age distribution, and the accompanying molecular and/or cytogenetics. The input on the disease side seems thin in the proposal as it is written. During any planning phase, attention needs to be placed on samples, their characteristics, etc—without that, it will not be possible to know what sorting approaches should be used to isolate CSC populations. Reviewer Two Comments Concept: Much current emphasis is focused on identification of drugs that target tumor initiating cells (CSCs). In keeping with this, the aim of the current proposal is focused on the identification of anti-CSC therapeutics. The approach to identify such compounds is based on what the PI, Dr Esmaeli-Azad, terms ‘CSC modeled niche based screening’. The design of this approach appears to be based on the notion that CSC, like their normal counterparts, are regulated by interactions with their microenvironmental niche, and thus screening for agents that target CSCs should be performed ‘in context’. This concept has merit. Proof of concept for this system is alluded to in the form of studies performed using AML CSC as the target. Insufficient detail is presented to allow adequate evaluation of this screening assay. With multiple spots per well which in addition to cell extracts and ECM proteins include soluble factors, how are spill-over effects prevented and/or minimized? Translation to screening CSC from other tumor types presupposes knowledge of the nature and composition of their niches. In many cases very little information is known of the composition of SC niches in normal tissues, let alone in tumors. This suggests a significant constraint in the capacity to translate this niche based screening technology broadly to CSC from diverse tissues. No indication is clearly given as to which tumor cell types will be targeted. Principal Investigator: The PI Dr Esmaeli-Azad is currently founder and President of DNAmicroarray, Inc. He has worked mainly in industry with an apparent focus on functional genomics and microarray based technologies. The capacity of the PI to lead the development of the research plan is difficult to evaluate. Planning Approach: The PI has enlisted collaboration with individuals from academia and mainly from industry. The role/contribution of the individual collaborators is not precisely defined although many will participate in small molecule screens, structure based design and medicinal chemistry, etc., approaches. Some are in Buenos Aires others in Maryland. How will these collaborators be enfolded within the disease team? A vast amount of work is proposed under the Preclinical studies, Clinical studies, FDA engagement, etc., without mentioning the specific tumor(s) to be targeted. It is not clear that all the necessary skill sets are to be found amongst the collaborators. The planning process does not appear to be well thought out and is insufficiently detailed.