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Exelixis, Inc. Message Board

  • wilderguide wilderguide Mar 29, 2014 9:35 AM Flag

    Tumor-educated bone induces therapeutic resistance

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    This study introduces the phenomenon of "osteocrines" - therapeutically activated bone secretions that may initiate the cascade of what is known as treatment-induced resistance. This work may redefine researcher understanding of the resistance mechanism. Most interesting of all - the trial designers have chosen Cabo response as their.study model, I suspect due to the striking early bone response. Check it out at the MDACC website - this work is funded by a SPORE grant:
    "Project 2: Osteocrines in Therapy Resistance of Prostate Cancer Bone Metastasis"
    For those paying attention, I feel there are lots of future implications in this research.
    GLTA

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    • "Resistance to cabozantinib rapidly occurs in both our model system as well as humans." This bothers me!It sure seems to a negative for Cabo and the others for that matter?
      Cabozantinib demonstrates striking clinical and radiologic responses in mCRPC patients with bone metastasis. However, as with other therapeutic agents, resistance to cabozantinib rapidly occurs in both our model system as well as humans…. Preliminary results showed that while cabozantinib reduces PCa-118b tumor growth, a “resistance niche” is present, in which viable p-MET positive tumor cells are found in proximity to newly formed bone. … We hypothesize that the resistance niche consists of osteocrines secreted from tumor-induced bone. … Our objectives are to (1) identify specific osteocrines that confer resistance to cabozantinib treatment; and (2) perform preclinical and then clinical trials to identify inhibitor combinations that will overcome resistance to cabozantinib.
      While resistance to cabozantinib is used as a study model, the results from the proposed study will be able to apply to other therapies, e.g docetaxel or cabazitaxel.
      So say they find out how to stop the osteocrines secreted fluid.Would that then mean the other two drugs would be used and work so much better that Cabo would be left out in the cold?

      • 1 Reply to clemcaldwell
      • $$$$
        "However, as with other therapeutic agents, resistance to cabozantinib rapidly occurs in both our model system as well as humans...(would that mean) that Cabo would be left out in the cold?"
        Good point, Clem... And I have to admit, I had reservations in posting that MDACC trial info...and for the very point you mention. Interpreting durability results in the absence of actual trial reporting is difficult. EXEL has really only given outlier info wrt durability of response, and the difficulties of making inferences has made this a risky bet. That said, treatment-induced resistance is not specific to Cabo, and is a problematic orientation in many cancer therapeutics. As popular as VEGF treatment has become, it's durability is limited...and Cabo seems to work in VEGF-resistant populations. I'm trying to keep unreported DOR in context, yet keep an eye on it. Undeniably, durability of response and overall survival are proportionately linked...Wish I could offer you more reassurance, but there it is.

    • Partial quote from and link to study that wilderguide cites. Seems like a positive that MDACC focuses on cabo: .“Metastatic cancer in bone is, in general, resistant to therapy as responses to therapies are usually incomplete and of short duration. … To study resistance specifically due to osteoblastic metastases, we use … a bone metastasis sample from a patient … We have used this model to study resistance to cabozantinib. … Cabozantinib demonstrates striking clinical and radiologic responses in mCRPC patients with bone metastasis. However, as with other therapeutic agents, resistance to cabozantinib rapidly occurs in both our model system as well as humans…. Preliminary results showed that while cabozantinib reduces PCa-118b tumor growth, a “resistance niche” is present, in which viable p-MET positive tumor cells are found in proximity to newly formed bone. … We hypothesize that the resistance niche consists of osteocrines secreted from tumor-induced bone. … Our objectives are to (1) identify specific osteocrines that confer resistance to cabozantinib treatment; and (2) perform preclinical and then clinical trials to identify inhibitor combinations that will overcome resistance to cabozantinib. While resistance to cabozantinib is used as a study model, the results from the proposed study will be able to apply to other therapies, e.g docetaxel or cabazitaxel.” See www.mdanderson.org/education-and-research/research-at-md-anderson/early-detection-and-treatment/research-programs/spores/prostate-cancer-spore/research/index.html.

      Sentiment: Hold

      • 1 Reply to jamer3651
      • $$$$
        To date, EXEL has been somewhat stingy - not only with OS data - but also with durable objective response (DOR) data. I simply feel it's a good idea to keep a watch for studies that may prove revealing in either endpoint. An advance heads-up on either OS or DOR data could prove worth it's weight in gold. Dana-Farber, MSKCC, Helen Diller, and MDACC are all on my DD watch list. Ya just never know where that next great idea might come from...
        GL

 
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