Articles about numerous potential ALK inhibitor drugs

These articles are overview or summary articles that discuss 3 of more potential drugs that may inhibit the growth of ALK + tumours.

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4 Responses to Articles about numerous potential ALK inhibitor drugs

  1. admin says:

    This April 2011 article covers 11 different ALK inhibitors (see Table 2) including some that are no longer being actively pursued.

  2. 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.

    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.

  3. admin says:

    This November 2011 article on ALK inhibitors has a list of 10 potential drugs to treat the ALK fusion mutation . The article disscuss several of these drugs in some detail.

  4. admin says:

    This podcast talks about screening issues and possible 2nd generation drugs for treating ALK+ patients who have become resistant to Crizotinib (all of which are mentioned on this website).

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