Help, fast growing tumors, which B Raf?

Gracie,

You are either missing Tumor-specific antigens, the right receptors, or  the "Danger Siganal"

Two major categories of melanoma metastases have been observed.

One subgroup of patient has an inflamed phenotype that includes expression of chemokines, T-cell markers, and other immunoregulatory factors. Clinical responders to melanoma vaccines appear to fall within this subset. This group also contains the highest expression of negative regulatory factors, including PD-L1, IDO, and FoxP3, suggesting that these immunosuppressive mechanisms may dominantly inhibit anti-tumor –cell function in those patients. In addition, absence of B7 expression supports classical T-cell anergy. Preclinical experiments have confirmed a critical role for these mechanisms in limiting anti-tumor T–cell efficacy in vivo, giving candidate treatment strategies for translation back into the clinic.

A second subset of patients is represented by tumors which are non-inflamed and lack chemokines for T cell recruitment. Therefore, a major barrier in these cases appears to be failed T –cell migration into tumor sites. Experimental strategies to augment T-cell migration can have important anti-tumor effects in preclinical models. The presence of the "inflamed" gene signature was associated with a type I IFN transcriptional profile, and murine experimental models have confirmed a critical role for type I IFN signaling in promoting adaptive immunity."

So,In the first subset, tumors had a suppresive nature that may be over riddden by Anti-CTLA-4 (Yervoy) and or Anti-PD-1 Therapy

The second subset was missing the "danger signal" inflammatory cytokines and chemoattractants most likely due to STAT3 signaling from the Tumor.

Stimulation of Toll-like receptor 4 (TLR-4) activates macrophages and results in the release of TNF-alpha. It is hypothesized that melanoma inhibits macrophage activation by suppressing TLR-4 signaling.

Now might be the time for a critical re-evaluation of our overall approaches to targeting STAT3 and for developing new models for disrupting the protein in order to accomplish the goal of delivering clinically useful direct STAT3 inhibitors as novel anticancer agents in a timely manner.

Gracie, you might want to ask you oncologist about  a STAT3 inhibitor with DTIC (alkylating agent) or radiation.

http://1.bp.blogspot.com/-p2-pK7X4kHg/Trmoxvm_ShI/AAAAAAAAAms/kngAUN2Z-2c/s1600/STAT3%2Band%2Binflammation.jpg

If you can't get a STAT3 inhibitor, I would try to get the GSK Braf + MEK therapy first. This blocks two pathways that the Melanoma can take.

If not, then  GSK Braf or Vemurafenib (also known as PLX4032, RG7204 or RO5185426, marketed
as Zelboraf.) with a mTOR inhibitor.

You might want to do the BRAF GSK or Zelboraf as a mono-therapy as the last resort.

You are going to need to lower your Tumor burden.

Please let us know your path forward with your Oncologist.

Warm regards,

Jimmy B

Gracie,

You are either missing Tumor-specific antigens, the right receptors, or  the "Danger Siganal"

Two major categories of melanoma metastases have been observed.

One subgroup of patient has an inflamed phenotype that includes expression of chemokines, T-cell markers, and other immunoregulatory factors. Clinical responders to melanoma vaccines appear to fall within this subset. This group also contains the highest expression of negative regulatory factors, including PD-L1, IDO, and FoxP3, suggesting that these immunosuppressive mechanisms may dominantly inhibit anti-tumor –cell function in those patients. In addition, absence of B7 expression supports classical T-cell anergy. Preclinical experiments have confirmed a critical role for these mechanisms in limiting anti-tumor T–cell efficacy in vivo, giving candidate treatment strategies for translation back into the clinic.

A second subset of patients is represented by tumors which are non-inflamed and lack chemokines for T cell recruitment. Therefore, a major barrier in these cases appears to be failed T –cell migration into tumor sites. Experimental strategies to augment T-cell migration can have important anti-tumor effects in preclinical models. The presence of the "inflamed" gene signature was associated with a type I IFN transcriptional profile, and murine experimental models have confirmed a critical role for type I IFN signaling in promoting adaptive immunity."

So,In the first subset, tumors had a suppresive nature that may be over riddden by Anti-CTLA-4 (Yervoy) and or Anti-PD-1 Therapy

The second subset was missing the "danger signal" inflammatory cytokines and chemoattractants most likely due to STAT3 signaling from the Tumor.

Stimulation of Toll-like receptor 4 (TLR-4) activates macrophages and results in the release of TNF-alpha. It is hypothesized that melanoma inhibits macrophage activation by suppressing TLR-4 signaling.

Now might be the time for a critical re-evaluation of our overall approaches to targeting STAT3 and for developing new models for disrupting the protein in order to accomplish the goal of delivering clinically useful direct STAT3 inhibitors as novel anticancer agents in a timely manner.

Gracie, you might want to ask you oncologist about  a STAT3 inhibitor with DTIC (alkylating agent) or radiation.

http://1.bp.blogspot.com/-p2-pK7X4kHg/Trmoxvm_ShI/AAAAAAAAAms/kngAUN2Z-2c/s1600/STAT3%2Band%2Binflammation.jpg

If you can't get a STAT3 inhibitor, I would try to get the GSK Braf + MEK therapy first. This blocks two pathways that the Melanoma can take.

If not, then  GSK Braf or Vemurafenib (also known as PLX4032, RG7204 or RO5185426, marketed
as Zelboraf.) with a mTOR inhibitor.

You might want to do the BRAF GSK or Zelboraf as a mono-therapy as the last resort.

You are going to need to lower your Tumor burden.

Please let us know your path forward with your Oncologist.

Warm regards,

Jimmy B

Gracie,

You are either missing Tumor-specific antigens, the right receptors, or  the "Danger Siganal"

Two major categories of melanoma metastases have been observed.

One subgroup of patient has an inflamed phenotype that includes expression of chemokines, T-cell markers, and other immunoregulatory factors. Clinical responders to melanoma vaccines appear to fall within this subset. This group also contains the highest expression of negative regulatory factors, including PD-L1, IDO, and FoxP3, suggesting that these immunosuppressive mechanisms may dominantly inhibit anti-tumor –cell function in those patients. In addition, absence of B7 expression supports classical T-cell anergy. Preclinical experiments have confirmed a critical role for these mechanisms in limiting anti-tumor T–cell efficacy in vivo, giving candidate treatment strategies for translation back into the clinic.

A second subset of patients is represented by tumors which are non-inflamed and lack chemokines for T cell recruitment. Therefore, a major barrier in these cases appears to be failed T –cell migration into tumor sites. Experimental strategies to augment T-cell migration can have important anti-tumor effects in preclinical models. The presence of the "inflamed" gene signature was associated with a type I IFN transcriptional profile, and murine experimental models have confirmed a critical role for type I IFN signaling in promoting adaptive immunity."

So,In the first subset, tumors had a suppresive nature that may be over riddden by Anti-CTLA-4 (Yervoy) and or Anti-PD-1 Therapy

The second subset was missing the "danger signal" inflammatory cytokines and chemoattractants most likely due to STAT3 signaling from the Tumor.

Stimulation of Toll-like receptor 4 (TLR-4) activates macrophages and results in the release of TNF-alpha. It is hypothesized that melanoma inhibits macrophage activation by suppressing TLR-4 signaling.

Now might be the time for a critical re-evaluation of our overall approaches to targeting STAT3 and for developing new models for disrupting the protein in order to accomplish the goal of delivering clinically useful direct STAT3 inhibitors as novel anticancer agents in a timely manner.

Gracie, you might want to ask you oncologist about  a STAT3 inhibitor with DTIC (alkylating agent) or radiation.

http://1.bp.blogspot.com/-p2-pK7X4kHg/Trmoxvm_ShI/AAAAAAAAAms/kngAUN2Z-2c/s1600/STAT3%2Band%2Binflammation.jpg

If you can't get a STAT3 inhibitor, I would try to get the GSK Braf + MEK therapy first. This blocks two pathways that the Melanoma can take.

If not, then  GSK Braf or Vemurafenib (also known as PLX4032, RG7204 or RO5185426, marketed
as Zelboraf.) with a mTOR inhibitor.

You might want to do the BRAF GSK or Zelboraf as a mono-therapy as the last resort.

You are going to need to lower your Tumor burden.

Please let us know your path forward with your Oncologist.

Warm regards,

Jimmy B

Do you know where that combo is offered and why it would be advantageous for me? BRAF + MEK

Gracie,

There is clinical data that suggests that by doing the BRAF + MEK, you can extend deasese free survival long than BRAF, as a Mono-Therapy.

Jimmy B

Clinical Trial NCT01072175

Clinical Trial NCT01072175

Clinical Trial NCT01072175

Do you know where that combo is offered and why it would be advantageous for me? BRAF + MEK

Gracie,

There is clinical data that suggests that by doing the BRAF + MEK, you can extend deasese free survival long than BRAF, as a Mono-Therapy.

Jimmy B

Do you know where that combo is offered and why it would be advantageous for me? BRAF + MEK

Gracie,

There is clinical data that suggests that by doing the BRAF + MEK, you can extend deasese free survival long than BRAF, as a Mono-Therapy.

Jimmy B