Post by Allen on Jul 29, 2014 21:20:02 GMT -8
Tyrosine Kinase Inhibitors (TKI)
There are about a dozen different tyrosine kinase inhibitors in clinical trials now for PC, and dozens more for other cancers. They represent one of the hottest areas of cancer research right now. They work by inhibiting certain growth factors within the cancer cell. They are usually used in conjunction with other cancer therapies like hormones and chemo, and they can be combined. Many act by blocking angiogenesis (see other thread).
The hottest one for PC is called cabozantinib (or Cometriq, formerly XL 184) and seems to clear bone mets in some men almost miraculously in 12 weeks. Exelixis tried to get early FDA approval for it based on relief of bone pain, but the FDA insisted on a demonstrated survival advantage and asked for a lower dose to improve tolerability. As Cometriq, approved for medullary cancer, it can be prescribed off-label. It’s in Phase 3 trials now. Several other TKIs have already been approved for other cancers, but none yet for PC. Cometriq and those others could potentially be prescribed “off-label.” However, it is possible that using one now may preclude getting one in a clinical trial later. Off-label new drugs like this are very expensive, and it is unlikely that insurance will cover them.
The TKIs that are already approved for other cancers and are in clinical trials now for PC include: Axitinib (Inlyta), Erlotinib (Tarceva), Gefitinib (Iressa), Imatinib (Gleevec), Sorafenib (Nexavar).
They are not all effective. Dasatinib (Sprycel) has failed to show a benefit when combined with docetaxel. Sunitinib (Sutent) failed to show a benefit over prednisone in mCRPC.
PC uses Interleukin-6 (IL6), an immune cytokine, to protect itself, and seems to interfere with TKIs. Immunosuppressors like mTOR inhibitors (see other thread) may suppress IL6 and may work synergistically in a cocktail with TKIs. Corticosteroids, which are usually included in these cocktails, may help also. There is a monoclonal antibody in clinical trials, Siltuximab, designed to suppress IL6.
In addition to stimulating the ERβ and inhibiting angiogenesis, soy isoflavones may also act as TKIs.
Here are some references:
Neoadjuvant Axitinib in Prostate Cancer
Erlotinib has moderate single-agent activity in chemotherapy-naïve castration-resistant prostate cancer
Additive antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), and the nonsteroidal antiandrogen, bicalutamide (Casodex), in prostate cancer cells in vitro
Phase I study investigating the safety and feasibility of combining imatinib mesylate (Gleevec) with sorafenib in patients with refractory castration-resistant prostate cancer.
A phase II study of sorafenib in combination with bicalutamide in patients with chemotherapy-naive castration resistant prostate cancer
Safety
Cometriq has been associated with fatal hemorrhages, GI perforations and fistulas in a small percent of cases. There is increased risk of thromboembolism and immune impairment. Here's a further caution about drug-drug interactions:
Drug—drug interactions with tyrosine-kinase inhibitors: a clinical perspective
There are about a dozen different tyrosine kinase inhibitors in clinical trials now for PC, and dozens more for other cancers. They represent one of the hottest areas of cancer research right now. They work by inhibiting certain growth factors within the cancer cell. They are usually used in conjunction with other cancer therapies like hormones and chemo, and they can be combined. Many act by blocking angiogenesis (see other thread).
The hottest one for PC is called cabozantinib (or Cometriq, formerly XL 184) and seems to clear bone mets in some men almost miraculously in 12 weeks. Exelixis tried to get early FDA approval for it based on relief of bone pain, but the FDA insisted on a demonstrated survival advantage and asked for a lower dose to improve tolerability. As Cometriq, approved for medullary cancer, it can be prescribed off-label. It’s in Phase 3 trials now. Several other TKIs have already been approved for other cancers, but none yet for PC. Cometriq and those others could potentially be prescribed “off-label.” However, it is possible that using one now may preclude getting one in a clinical trial later. Off-label new drugs like this are very expensive, and it is unlikely that insurance will cover them.
The TKIs that are already approved for other cancers and are in clinical trials now for PC include: Axitinib (Inlyta), Erlotinib (Tarceva), Gefitinib (Iressa), Imatinib (Gleevec), Sorafenib (Nexavar).
They are not all effective. Dasatinib (Sprycel) has failed to show a benefit when combined with docetaxel. Sunitinib (Sutent) failed to show a benefit over prednisone in mCRPC.
PC uses Interleukin-6 (IL6), an immune cytokine, to protect itself, and seems to interfere with TKIs. Immunosuppressors like mTOR inhibitors (see other thread) may suppress IL6 and may work synergistically in a cocktail with TKIs. Corticosteroids, which are usually included in these cocktails, may help also. There is a monoclonal antibody in clinical trials, Siltuximab, designed to suppress IL6.
In addition to stimulating the ERβ and inhibiting angiogenesis, soy isoflavones may also act as TKIs.
Here are some references:
Neoadjuvant Axitinib in Prostate Cancer
Erlotinib has moderate single-agent activity in chemotherapy-naïve castration-resistant prostate cancer
Additive antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), and the nonsteroidal antiandrogen, bicalutamide (Casodex), in prostate cancer cells in vitro
Phase I study investigating the safety and feasibility of combining imatinib mesylate (Gleevec) with sorafenib in patients with refractory castration-resistant prostate cancer.
A phase II study of sorafenib in combination with bicalutamide in patients with chemotherapy-naive castration resistant prostate cancer
Safety
Cometriq has been associated with fatal hemorrhages, GI perforations and fistulas in a small percent of cases. There is increased risk of thromboembolism and immune impairment. Here's a further caution about drug-drug interactions:
Drug—drug interactions with tyrosine-kinase inhibitors: a clinical perspective
