Keeping you up to date on recent developments in oncology

NIH offers potential chemotherapeutic agent for licensing . . . The National Institutes of Health routinely offer their developments for licensing or co-development, and a notice in the Federal Register lists one such offering. According to NIH's announcement, investigators at the agency have “discovered a series of small compounds with the potential to treat a variety of cancers as well as hemolytic anemia,“ which take the form of “small molecules that activate pyruvate kinase isoform M2,“ dubbed PK-M2. This, NIH states, “is a critical metabolic enzyme that is affected in all forms of cancer,“ and the inactivation of this enzyme is said to lead to a buildup of metabolic intermediates inside a cell, a process said to be essential to the replication essential to carcinogenesis. Hence, these small molecules can be employed to activate PK-M2 and hence truncate the buildup of those metabolic intermediates, thereby either stalling the cancer or leading to the death of the affected cancer cell. Another benefit to this offering is that while other isoforms of the PK line of enzymes are active in many cell types, the M2 variant is the only active variant in tumors, hence making the product tumor-specific. The pharmacores that are the heart of this invention can be used not only for therapeutic purposes, but also for diagnostics, NIH states. The invention is still in a preclinical developmental stage and is the subject of a provisional patent application. Parties interested in licensing opportunities can contact Steven Standley, PhD (301-435-4074, sstand@mail.nih.gov), while those interested in collaborative development should reach out to Matthew Boxer, MD (boxerm@mail.nih.gov).

Herringbone makes the most of the microfluidic chip . . . The microfluidic chip is one of the more promising of the recent developments in diagnostics, and researchers at Massachusetts General Hospital and Harvard Medical School (both Boston) were among the pioneers with their invention in 2007 of a microfluidic device that was able to trap the seemingly stray circulating tumor cell (CTC) in the blood of cancer patients. According to a statement at the website for the National Cancer Institute's Alliance for Nanotechnology in Cancer, two of the team involved in that effort, Mehmet Toner, PhD and Daniel Haber, MD, have been collaborating with their colleague from Harvard Medical, Shyamala Maheswaren, PhD, on a redesign of their first iteration that will enable capture of CTCs in sufficient numbers to characterize tumors from patients with lung and prostate cancer and, with a little luck, will enable physicians to use such technology “to determine if CTCs can serve as early indicators of disease and therapeutic efficacy.“ The latest development hinges on the redesign of the channels into a herringbone configuration – the classic zig-zag shape so well known to fashion designers – that should at the very least prove easier to manufacture than the first iteration. The new version of the original CTC-chip, dubbed the HB-(herringbone) chip, may offer other advantages as well. Shannon Stott, PhD, one of the authors of the paper appearing in the Proceedings of the National Academies of Sciences that describes the work, said in the statement that the original chip “worked wonderfully in a small-scale laboratory setting, but limitations arose when we attempted to increase production for larger clinical studies.“ Stott added, however, that the newer version “performs as well or better than the previous technology with several additional benefits.“ One of these is that the herringbone configuration allows the chip “to capture something that had never been seen using either the CTC-chip or the most prevalent previous technology – small clusters of CTCs, the significance of which we need to study.“ This development is stretching the current understanding of cancer development because CTCs are so rare in the human blood stream that until the advent of the 2007 chip, “it was not possible to get information from CTCs that would be useful for clinical decision making,“ the NCI statement notes. Samples of serum in the original configuration bound to microscopic posts coated with an antibody in sufficient numbers to confirm the general idea, but the difficulty of reliably and inexpensively manufacturing the units drove an interest in a better design. Another factor was that the configuration of the channels provided insufficient turbulence to maximize the exposure of CTCs to the antibody-lined posts, thus limiting the effectiveness of the design. However, the herringbone pattern, said to be a design element used in another application for rapid mixing of independent fluid streams, imparted greater turbulence “that could significantly increase the number of captured cells,“ according to the NCI statement. The larger volume of the herringbone configuration offers another advantage, namely that it allows the processing of larger volumes of blood, which further increases the number of CTCs that can be detected. One of the potentially ground-breaking developments associated with the redesign is that the 25% increase in CTC pick-up has led to a greater detection of cell aggregates in clusters of four to 12 CTCs. While the significance of this finding is not yet understood, a more clear understanding may say something about how cancers metastasize. Finally, the use of clear glass slides allows a clinician to use the slides for further analysis and culturing. Toner states in the NCI statement that the cell clusters “may have broken off from the original tumor, or they might represent proliferation of CTCs within the circulation,“ adding that a better understanding of this phenomenon “could provide valuable insight in the metastatic process.“ This research appears in a paper titled “Isolation of circulating tumor cells using a microvortex-generating herringbone chip,“ and was supported in part by the NCI Alliance for Nanotechnology in Cancer.

UK researchers tie estrogen-dependent breast cancer to a single gene . . . Finding a single gene that is responsible for an entire class of cancer is perhaps too much to ask, but researchers in the UK have pinpointed a single gene they believe is responsible for all estrogen response-dependent breast cancers. According to a Dec. 12 statement at the website for Cancer Research UK (London), scientists working at the organization's Cambridge Research Institute have pegged a gene known as FOXA1 as the mechanism by which estrogen receptors are able to interact with the DNA inside breast cancer cells, switching on genes that trigger unchecked cell growth. With any luck, the finding will lead to development of drugs that will treat breast cancer in women who do not respond to tamoxifen, which blocks the estrogen receptors in some cancer cells, but does not work exhaustively in that fashion, leaving about a third of patients with no benefit or with a risk of relapse after some initial benefit. Jason Carroll, MD, the lead author of the article explaining the development in the journal Nature Genetics, said in the statement that he and his colleagues “discovered that almost none of the genes normally switched on by estrogen receptors interacting with the DNA were activated in breast cancer cells lacking FOXA1.“ Instead, he said, the estrogen receptor “was just left floating around in the cell, unable to make contact with the DNA and kick-start cell growth.“ Because tamoxifen also uses FOXA1 to interact with DNA, the researchers have concluded that “developing drugs to block FOXA1 could provide an effective treatment for women with ER positive breast cancers who have become resistant to standard hormone treatments, like tamoxifen,“ Carroll said. Breast cancer is said to be the most common cancer in the UK, responsible for more than 45,000 diagnoses each year, with about two thirds of those diagnosed as hormone-sensitive breast cancers. Lesley Walker, MD, director of cancer information at Cancer Research UK, said in the statement that researchers “know that some women with breast cancer stop responding to tamoxifen, making them more prone to relapsing. This important discovery could one day lead to new drugs that help improve the outcome for these patients.“

Compiled by Mark McCarty, MDD Washington Editor
mark.mccarty@ahcmedia.com