Other Drugs

A place to post info on other potential drugs for which there is no specific page or for posting research that covers two or more different drugs.

This entry was posted in Anaplastic Large-Cell Lymphomas, Glioblastomas, Lung cancer, Neuroblastomas, Potential Treatments, Research and tagged . Bookmark the permalink.

23 Responses to Other Drugs

  1. admin says:

    One article and two abstract’s refer to an ALK inhibitor called WHI-P154.

    An Aug. 2011 article by researchers in Taiwan studies WHI-P154. In it the drug was given to mice by I.V. They discuss the implications of the fact that WHI-P154 also inhibits STAT3 which is a downstream signaling kinase from ALK. The look at 6 point mutations of ALK and test the strongest 2 against WHI-P154. When exposed to the drug the tumors grow more slowly and metastasis less. Here is the link: http://www.neoplasia.com/pdf/manuscript/v13i08/neo11222.pdf

    This link is from Dec. 2011 to an abstract that appears to be related to the article and indicates the drug was tested in mice and caused tumors to shrink: https://docs.google.com/viewer?a=v&q=cache:yVkTweDgQnEJ:db1n.sinica.edu.tw/textdb/papago/en/report/fileReportBrief.php?rid%3D14682+alk+inhibitor&hl=en&gl=us&pid=bl&srcid=ADGEEShL39yBl3Ilkbnubb1xjffsK00Pmla1iQwOfqW0Z8vmxu0vWi0QIIntjzeCnkq-jc1FSgSxbfrpGxQWT_NQokv_PhdVdv3b2i0jpgbgE3wn6_7STKhloaqtpnoykcqP3PX1_KGa&sig=AHIEtbRjTfycKrZgwpBAXF1jdBUn3gMLZQ

    This abstract is from Sept. 2005 by a University of Pennsylvania team working with other academics: http://www.nature.com/labinvest/journal/v85/n12/full/3700348a.html

  2. admin says:

    Italian researchers from Nerviano Medical Sciences have developed NMS-E628 as a potential ALK inhibitor.

    As of January 2012, Nerviano has posted on their website that they are close to filing a new drug application. http://www.nervianoms.com/en/oncology-en/pipeline/preclinical-programs.html

    In November 2011 there was a presentation on “In vitro and in vivo activity of NMS-E628 against ALK mutations resistant to Xalkori” Here is the link http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=df62cef8-2afd-4abd-a333-e99c6424260e&cKey=fa5556a3-5f93-401d-9314-0a39bd217795&mKey=%7bA57FF86D-D414-4079-BCBD-157746574F37%7d
    According to the abstract NMS-E628 was able to overcome the mutations L1196M and C1156Y in mouse studies.

    The article below is from Nov. 2009. According to the abstract, this drug is able to cross the blood brain barrier in different species.

    http://mct.aacrjournals.org/cgi/content/meeting_abstract/8/12_MeetingAbstracts/A244

  3. admin says:

    PharmaDesign has identified several ALK inhibitors using a virtual computer screen of a public chemical library at the University of Tokyo. See the link below for more details.

    http://www.ncbi.nlm.nih.gov/m/pubmed/21515061/

  4. admin says:

    Xcovery has announced that their drug, x396, is ten times more potent than Crizotinib and that “x396 has shown activity in ALK mutations that confer resistance to” Crizotinib. Xcovery also announced that they will be starting a Phase 1 clinical trial of x396 by the end of 2011. Now pushed back to 1st quarter 2012.
    For more details see: http://www.xcovery.com/alk/

    Here is an article about x396:
    http://cancerres.aacrjournals.org/content/71/14/4920

  5. admin says:

    Children’s Hospital of Philadelphia has done in vitro research on an anti-ALK antibody approach for treating ALK positive Neuroblastomas. Apparantly when combined with Crizotinib the treatment is more effective than either treatment on its own.

    See the following link for more details: http://www.nbglobe.com/2011/04/08/aacr-2011-a-new-antibody-approach-for-neuroblastoma/

  6. admin says:

    Tesaro (a biotech startup) has entered into an exclusive agreement to bring to market ALK inhibitors developed by Amgen. The press release describes the drugs as “highly potent and selective, and possess desirable pharmeceutical properties.” Tesaro says it “intends to rapidly complete the necessary studies and activities required for submission of [a new drug] application” to the FDA. Another article indicates the application is likely to occur in 2012.

    See here for the press release: http://tesarobio.com/tesaro-enters-into-exclusive-license-agreement-with-amgen-to-acquire-rights-to-anaplastic-lymphoma-kinase-alk-program/

  7. DavidF says:

    This relates to the mouse research below (October 25, 2010 at 3:18 pm).
    HSP-90 inhibitor IPI-504 from Infinity Pharmaceuticals effective in very small group of ALK+ patients in clinical trial. Don’t know if this is covered elsewhere on this web site. Together they make a strong case that ALK+ patients with resistance to Crizotinib should enroll in any one of the HSP-90 inhibitor trials.

    See the Nov 24 post on http://cancergrace.org/lung/
    full link:
    http://cancergrace.org/lung/2010/11/24/heat-shock-protein-inhibitor-ipi-504-particularly-active-for-patients-with-an-alk-rearrangement/

  8. admin says:

    There is a phase II clinical trial to test the effectiveness of UCN-01 in treating relapsed T-Cell Lymphomas. A secondary outcome that is being tested is the “effect on anaplastic lymphoma kinase (ALK) expression in patients with anaplastic large cell lymphoma.”

    http://www.clinicaltrials.gov/ct2/show/NCT00082017?term=anaplastic+lymphoma+kinase&rank=9

    From the phase I trial – one protracted period ( > 2.5 years) of disease stability was observed in a patient with alk-positive anaplastic large-cell lymphoma.

    However a follow up study was done on UCN-01 and the found that “The low potency of UCN-01 and its lack of specificity for NPM/ALK transformed cells in proliferation assays (data not shown) suggest that UCN-01 does not target ALK. Therefore, potent and specific ALK inhibitors still need to be developed.”

    See http://www.haematologica.org/cgi/reprint/90/7/988.pdf

  9. admin says:

    Here is an abstract for an October 2010 article by researchers at Harvard that compares four different approaches for treating ALK positive lung cancer. The full article is available for $35.

    http://www.ncbi.nlm.nih.gov/pubmed/20952506

    In particular the researchers used ALK+ mice to compare the effectiveness of: 1) chemotherapy, 2) kinase inhibitors for several kinases that are downstream of the ALK kinase, 3) an ALK inhibitor, and 4) a heat shock protean 90 inhibitor. The drugs tested were 1) carboplatin & paclitaxel, 2)AZD6244, BEZ-235, and WZ4002, 3) NVP-TAE684, and 4) 17-DMAG.

    The researchers found that the ALK inhibitor was very effective and the HSP90 inhibitor was second most effective. Chemotherapy and the downstream kinase inhibitors had about the same level of minimal effectiveness.

    In greater detail, “all of the TAE684 treated mice achieved complete regression within 2 weeks.” Furthermore, “To date [~75 weeks], drug resistant tumors have not developed.”

    In mice, 17-DMAG resulted in a “average of 84% tumor regression within one week of treatment.” However, “tumor response was not durable, and varied significantly among mice during treatment.” On the positive side, 17-DMAG “tripled the survival of treated mice” as compared to untreated mice.

    Chemotherapy “resulted in only a modest reduction in tumor volume (17-27%) [after] 2 weeks” of treatment. “Resistance rapidly developed, and the tumors progressed and exceeded the original tumor burden in 5 weeks.”

    The most unexpected results of the research related to the fourth option of inhibiting several downstream kinases. The theory is that when the ALK enzyme is “turned on” that it passes a signal “downstream” through several other kinases in order to actually turn on certain genes, which is what causes the cancerous growth. Three of the most important downstream kinases are P13K, mTOR, and MEK. The researchers were able to successfully stop cell growth in test tubes by inhibiting these three kinases (with two inhibitors). However, when they tested the same inhibitors in mice, they were only able to achieve “tumor regression of ~20%” (about the same as chemotherapy). According to the article the same combination of inhibitors was able to cause substantial tumor regression for EGFR lung cancer tumors in mice. This suggests that there is at least one other signaling pathway that is triggered by ALK (but not EGFR). In fact, the researchers even tried an additional inhibitor (of the JAK kinase) to see if that would work, but it did not. So this leaves open the possibility of yet another ALK triggered signaling pathway. However, it remains unclear why these inhibitors worked in the test tub but not in mice.

  10. admin says:

    According to the October 2010 annual report for Sareum Holdings, PLC they “are developing joint Aurora/ALK kinase inhibitors”

    see http://www.sareum.co.uk/base/images/pdfs/Sareum_Results_2009-10.pdf

  11. Kirkwood says:

    Here is a June 2009 abstract about two multikinase inhibitors with activity against ALK. They are F91873 and F91874. They inhibited cell proliferation in three ALK+ cell lines. “Furthermore, administration of F91874 to severe combined immunodeficient mice bearing COST tumor xenografts resulted in a significant antitumor efficacy.” The researchers were from France.

    See http://www.ncbi.nlm.nih.gov/pubmed/19322071

  12. admin says:

    Italian researchers appear to have designed a ALK inhibitor called PHA-E429.

    Here is a July 2010 link to an abstract of an article in which they model in three dimensions how their inhibitor interacts with the ALK gene. http://pubs.acs.org/doi/abs/10.1021/bi1005514

  13. admin says:

    French researchers have “designed and developed four chemical scaffolds that are able to inhibit ALK activity with IC50 in the nanomolar-low micromolar range.”
    Here is a September 2010 link to a technology licensing offer: http://www.us-eu-match.com/index.cfm?action=article&publication_id=30596&appId=2&is_article=1

  14. admin says:

    Japanese researchers have found that All-trans retinoic acid “downregulates ALK in neuroblastoma cell lines” which “was accompanied by apoptosis [cell death] in neuroblastoma cells” Here is a link to a Nov. 2010 abstract.

    http://www.ncbi.nlm.nih.gov/pubmed/20576349

  15. admin says:

    GlaxoSmithKline has developed an ALK inhibitor (GSK1838705A). “GSK1838705A inhibits ALK … and causes complete regression of ALK-dependent tumors in vivo at well-tolerated doses.” “however, the sustained hyperinsulinemia in mice treated for 23 days .. suggests that caution is warranted with chronic dosing.”
    Here is a link to a October 2009 abstract http://mct.aacrjournals.org/content/8/10/2811.abstract

    here is a link to the full article
    http://mct.aacrjournals.org/content/8/10/2811.full.pdf+html

  16. admin says:

    Here is a May 2010 article that mentions four drugs that are being developed to inhibit ALK. These include Crizotinib (currently in Phase III testing), CEP-28122 (FDA clinical trial application due in 2010), AP-26113 (FDA clinical trial application due 2011), and X-276 (preclinical).

    It also mentions a drug (GSK-2141795 (in phase 1 trial)) that has been developed to inhibit AKT (a downstream kinase in the ALK signaling pathway).

    http://www.lcfamerica.org/blog/wp-content/uploads/ALK-Lung-Cancer-and-Personalized-Therapy-JNCI-2010.pdf

  17. admin says:

    Here is a link to the pipeline page of a start up company called Xcovery. They have a drug called X-276 that is in pre-clinical development.

    http://www.xcovery.com/productpline.htm

  18. admin says:

    Some French researchers did a study on the Matrix Metalloproteinase-9 (“MMP-9”) inhibitor called GM6001. “The MMP inhibitor GM6001 and MMP-9 blocking antibodies abolished the invasiveness of NPM-ALK(+) cells.” The test was done on anaplastic large cell lymphoma. “[O]ur observations strengthen the concept that chaperones have a major extracellular role in the regulation of protein activation status, and reveal new factors that are crucial for spreading and invasion of ALK(+) ALCL.”

    See http://cancerres.aacrjournals.org/content/70/17/6978.abstract

  19. admin says:

    The National Cancer Institute did a study on Perifosine (which is an AKT inhibitor) and published their results in May 2010. They found that “the growth of neuroblastoma tumors containing ALK mutations, or over-expression of ALK, is inhibited by perifosine.” The test was done in mice.

    See http://www.cancer.gov/newscenter/pressreleases/Perifosine

    See also http://jnci.oxfordjournals.org/content/102/11/758.abstract

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