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Exelixis, Inc. Message Board

  • wildbiftek wildbiftek Oct 26, 2013 12:02 AM Flag

    Cabozantinib Inhibits Growth of Androgen-Sensitive and Castration-Resistant Prostate Cancer and Affects Bone Remodeling

    A deep dive into the effects of Cabo on Prostate cancer:

    Cabo Resistance:

    "Interestingly, there are remaining foci of healthy tumor cells adjacent to the necrotic areas, suggesting involvement of angiogenesis and also indicating that the treatment did not constitute a cure, and possibly continuous treatment might be needed to control the disease progression. Notably this was true for androgen-sensitive as well as castration-resistant tumors."

    Cross talk:

    In our study, however, we did not detect any significant associations between MET, P-MET or VEGFR2 with the levels of AR, PSA or PSMA in patient samples. Also, no significant associations between MET or P-MET and AR levels or responses to androgen ablation were revealed in 24 adenocarcinoma LuCaP xenografts examined in our study. Therefore our results do not indicate AR regulation of MET or any association with response to castration. This result agrees with a report showing that expression of MET examined by IHC did not appear to be increased in malignant prostate cells from patients who had undergone androgen ablation therapy compared to those who had not [10]. However, increased expression of MET was detected by qPCR in tumor samples from CRPC patients compared to metastatic non-castrate PCa patients [43]. It is important to note that both of the preclinical studies that report a link between AR signaling and MET employed cell lines in their studies (LNCaP and CWR22) [13,14], while we and those who have reported results in concordance with ours examined patient samples. Studies examining the expression levels of MET and other RTKs in the same patients before and after androgen deprivation and/or transition to castration resistance are needed to more definitively determine the roles and/or relationships of these receptors in the development and progression of primary PCa, as well as in the development of castration resistance.

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    • Note that this was an animal study so the dosing and tolerability isn't necessarily applicable in the same way to people. Furthermore, two of the authors were employees of Exelixis.

    • Mechanism of Cabo:
      To determine the target rationale for cabozantinib in advanced PCa, we first set out to examine the expression of MET and VEGFR2 and levels of P-MET in PCa metastases. Our results highlight MET and VEGFR2 as important targets in PCa metastases, especially in bone, as levels of MET, P-MET and VEGFR2 were significantly upregulated in PCa BM as compared to primary PCa. Furthermore, both of the receptors are also expressed in soft tissue metastases, indicating that MET and VEGFR2 play important roles in the progression of PCa in multiple metastatic settings. In addition, the expression profiles of all cabozantinib targets tested (MET, VEGFR2, AXL, RET, and KIT) in LuCaP PCa xenografts demonstrate that all of these targets are expressed in advanced PCa. The expression pattern in the xenografts is heterogeneous, suggesting that cabozantinib may be broadly applicable in PCa treatment. In concordance with our results with the LuCaP models, AXL, RET and KIT were also detected in advanced PCa in other studies [40-42].
      ...

      • 1 Reply to wildbiftek
      • One of our objectives was to investigate the mechanisms of cabozantinib effects on the tumor. Our analysis showed the presence of large necrotic areas in the tumors in bone and significant decreases in the volume of subcutaneous tumors. To demonstrate that the observed inhibitory effects of cabozantinib are due to inhibition of VEGFR2 and MET signaling one would like to demonstrate “on target effects” in vivo. However, the levels of VEGFR2 and MET were very low or undetectable in LuCaP 23.1 and C4-2B tumors, and because very little of the tumor tissue was available following cabozantinib treatment, we could not evaluate the on target effects by looking at decreases in phosphorylaiton of these targets. However, this does not indicate that the cabozantinib inhibition of tumor growth does not involve VEGFR2 and MET signaling alterations. It is certainly possible that cabozantinib does have inhibitory effects on the expected kinases even though in these studies, the kinase levels were below the IHC level of detection in the pre-treated xenografts. Even at these low levels, inhibition of these kinases could have a biological effect. As an alternative approach to examine potential mechanisms of cabozantinib effects, we used qPCR. Our results showed decreased levels of survivin and MYC, genes associated with tumor progression, and HIF1A and VEGFR2m, that are associated with tumor progression and angiogenesis in the cabozantinib–treated C4-2B tumors. These qPCR data, the expression of cabozantinib targets in PCa, and cabozantinib’s ability to inhibit multiple kinases, suggest that cabozantinib might affect tumor cells directly as well as indirectly via effects on the tumor microenvironment, and therefore might be effective across a broad spectrum of PCa phenotypes.

    • PSA:
      It is important to note that in the clinical situation cabozantinib treatment does not result in consistent decreases of PSA. In many patients PSA levels did not correlate with the reduction in tumor burden that resulted from cabozantinib treatment. Since the observed regression in soft tissue lesions suggests that cabozantinib may have an effect on tumors that is independent of bone environment, this finding is surprising. As such, it is necessary to delineate whether cabozantinib acts on the tumor and/or the microenvironment, and whether this efficacy is a function of androgen sensitivity. Our results agree with the clinical observations. Even though the PSA levels were lower in the treated group vs. the control group, the PSA levels were not lower in the majority of animals bearing intratibial tumors after treatment when compared to pre-treatment levels. Taken together, our data indicate that cabozantinib is efficacious in models of androgen-sensitive PCa as well as in CRPC, and show that cabozantinib efficacy does not solely depend on the bone microenvironment. These data are consistent with cabozantinib’s clinically beneficial observations in patients both with and without bony metastases.

      Bone remodeling in normal bone (I took this to mean mice with no tumor xenografts. They had two groups of these, castrate and non castrate):
      To evaluate the effects of cabozantinib on non-tumored bone, we analyzed the contralateral non-tumored tibiae of the treated and control animals by µCT. Our analyses show that cabozantinib treatment increased BV/TV in intact and castrated male mice; see TABLE 1. Representative examples of µCT images are shown in Figure 3B.

      • 1 Reply to wildbiftek
      • Bone cont:
        Because VEGFR2 and MET signaling are important in bone biology, it is clear that cabozantinib treatment may not only affect tumored bone, but potentially normal bone as well. Our results show that cabozantinib treatment resulted in increased BV in intact as well as castrated animals. Patients with CRPC are typically on ADT, which causes osteopenia and osteoporosis. Therefore, cabozantinib therapy might provide additional benefits to patients with advanced PCa who are on ADT. The systemic effect of cabozantinib on the skeleton might lead to decreased number of and time to skeletal related events in patients.

    • Tolerability:

      "The 60 mg/kg dose was well-tolerated in our preclinical models for four weeks of administration when tumors were growing in the bone; but body weight loss was observed with longer treatment. Interestingly the loss of body weight was more pronounced in animals bearing LuCaP 23.1 tumors than in those with C4-2B tumors. A lower dose of cabozantinib (30 mg/kg) was well-tolerated up to six weeks, and the animals lost less weight compared to those that received a higher dose. Therefore, we conclude that cabozantinib treatment is well-tolerated for 4-6 weeks with some negative effects on body weight after prolonged treatment of intra-tibial tumors."

      Conclusion:

      "In conclusion, we demonstrate that cabozantinib targets are expressed in advanced PCa, indicating that this treatment has the potential for substantial efficacy in the heterogeneous PCa population. Angiogenesis inhibition has not yielded significant advances in the treatment of CRPC to date, and a growing body of evidence suggests that signaling through MET may be a compensatory mechanism by which tumor cells escape anti-angiogenic therapy. Thus, since cabozantinib targets VEGFR2, MET and a number of other RTKs simultaneously, it represents an attractive, new opportunity in anti-angiogenic CRPC treatment. Furthermore, our results show that cabozantinib inhibits tumors in two different PCa: an androgen-dependent osteoblastic model and a castration-resistant mixed osteoblastic/osteolytic model. Furthermore, cabozantinib also affects tumors growing in the bone and subcutaneous tumors, again indicating the potentially high clinical impact of this treatment."

      • 2 Replies to wildbiftek
      • Thanks for the detailed update on your research. So many positives. Hopefully Cometriq will soon be approved to help extend the lives of cancer patients world-wide.

      • And yet the SP continues to languish as if they were selling liniment at a state fair. Somehow something doesn't add up.

        The ER this upcoming week could be either the straw that breaks the camel's back or the spark that lights the fuse on this rocket.

        It's been about 3 years since the we all saw those dramatic bone scan images of patients with tumors that disappeared. Many people have died waiting for the research to catch up with what our eyes saw. We've all lost loved ones to cancer of all sorts since then. The time draws nigh for all of us and I'm getting more tired and more frustrated by the day.

        Sorry for the morbid feel of this post but I recently lost a very dear friend and a sister and the feeling of helplessness is only heightened by my growing awareness of how difficult this process is, even in the year 2013.

        Sentiment: Strong Buy

 
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