.
"Ultimately, the research suggested that a combination of drugs blocking the PI3K, mTORC1/2 and MEK1/2 pathways represent the optimal combination for use with a BRAF inhibitor to mitigate the development of resistance. "
"All three compounds we used to overcome resistance to BRAF inhibition are already undergoing clinical evaluation. Therefore, we believe this particular combination approach represents a promising and translatable strategy for addressing BRAF inhibitor resistance in a subset of melanomas," Dr. Lo says.
"Among clinical trials currently enrolling melanoma patients with BRAF mutations are those combining BRAF and MEK inhibition and others combining PI3K/mTOR and MEK inhibition. Other highly-watched trials include those which combine a BRAF inhibitor with ipilimumab. "
Source: Dematology Times
"Ultimately, the research suggested that a combination of drugs blocking the PI3K, mTORC1/2 and MEK1/2 pathways represent the optimal combination for use with a BRAF inhibitor to mitigate the development of resistance. "
"All three compounds we used to overcome resistance to BRAF inhibition are already undergoing clinical evaluation. Therefore, we believe this particular combination approach represents a promising and translatable strategy for addressing BRAF inhibitor resistance in a subset of melanomas," Dr. Lo says.
"Among clinical trials currently enrolling melanoma patients with BRAF mutations are those combining BRAF and MEK inhibition and others combining PI3K/mTOR and MEK inhibition. Other highly-watched trials include those which combine a BRAF inhibitor with ipilimumab. "
Source: Dematology Times
Harry, I thinks the "Magic Bullet" will be a combinatorial therapy. It will most likely drugs strung in a sequence that :
1) A drug combo to make the tumor more susceptible to Chemo to shed Tumor-Specific antigens from dying tumor cells (DTIC,Patrin-2,Cisplatin,TMZ,radiation,biochemo..etc)
2) a drug combo to suppress the Tregs and help activate T-cells (Yervoy,Anti-PD-1, Anti-Gal-3 ..etc)
3) Finally a drug that keeps the T-cell (Cytotoxic T-lymphocytes) activated, functional and that is needed for survival.
10-24-2005 when I was first diagnosed with melanoma
10-27-2005 I had a wide incision to remove the tumor off my back
3-6-2006, I started the High Dose Interferon treatment
7-10-2006, I started my clinical trial of Dicarbazine and Patrin
9-13-06(day 1)I had my first and only infusion of anti-CTLA-4 monoclonal antibodies 15mg/Kg
11-1-06, the first cycle of High dose Interleukin-2 (IL-2).
(day98) 12-19-06 we got the CT Scan Results: What a Christmas Present!!!!!! The tumors were shrinking!!!!!!!
10-24-2005 when I was first diagnosed with melanoma
10-27-2005 I had a wide incision to remove the tumor off my back
3-6-2006, I started the High Dose Interferon treatment
7-10-2006, I started my clinical trial of Dicarbazine and Patrin
9-13-06(day 1)I had my first and only infusion of anti-CTLA-4 monoclonal antibodies 15mg/Kg
11-1-06, the first cycle of High dose Interleukin-2 (IL-2).
(day98) 12-19-06 we got the CT Scan Results: What a Christmas Present!!!!!! The tumors were shrinking!!!!!!!
10-24-2005 when I was first diagnosed with melanoma
10-27-2005 I had a wide incision to remove the tumor off my back
3-6-2006, I started the High Dose Interferon treatment
7-10-2006, I started my clinical trial of Dicarbazine and Patrin
9-13-06(day 1)I had my first and only infusion of anti-CTLA-4 monoclonal antibodies 15mg/Kg
11-1-06, the first cycle of High dose Interleukin-2 (IL-2).
(day98) 12-19-06 we got the CT Scan Results: What a Christmas Present!!!!!! The tumors were shrinking!!!!!!!
Harry,
Did you have inflammation 15 days after I was infused with Anti-CTLA-4?
Well I did. It is a tell tale sign that I vaccinated myself with help of Anti-CTLA-4. Self vaccinated with my own Tumor-Specific Antigen. This very simular to Dr. Rosenburg's ACT therapy, but my was all in vivo. How long will it last, No one can say.
The graph is backed up with science.
for instance:
"Chemotherapy induces intratumoral expression of chemokines in cutaneous melanoma, favoring T cell infiltration and tumor control"
In conclusion, the present study identifies CXCR3 ligands and CCL5 as the main determinants of
T cell infiltration into cutaneous metastases and shows that chemotherapy, by inducing
expression of these chemokines within human tumors, may trigger T cell infiltration and tumor
control, resulting in prolonged patient survival. Therefore, screening for chemotherapeutic
products able to induce the expression of T cell attracting-chemokines in cancer cells may
identify drugs that improve the efficacy of immunotherapy
Corresponding author: Jean-Pierre Abastado, Laboratory of Tumour Immunology, Singapore
Immunology Network, 8A Biomedical Grove, #04-06 Immunos, Singapore 138648.
Tel: +65 6407 0003.
Fax: +65 6464 2057.
EM: abastado@immunol.a-star.edu.sg
Email Dr. Abastado for a copy of his paper.
————————————————————————————————————-
Sensitization of a human ovarian cancer cell line to
temozolomide by simultaneous attenuation of the
Bcl-2 antiapoptotic protein and DNA repair by
O6-alkylguanine-DNA alkyltransferase
Introduction
"Temozolomide and or DTIC is an alkylating agent that mediates its cytotoxic effect by forming O6-methylguanine (O6-meG)DNA adducts, which during DNA replication pair preferentially with thymidine. These O6-meG:T mispairs can result in a G-to-A point mutation during a subsequent round of DNA replication but are also substrates for the postreplication mismatch repair pathway, which
fter a further round of DNA replication leads to apoptosis (1). O6-meG DNA adducts can be repaired by the DNA repair protein O6-alkylguanine-DNA alkyltransferase (MGMT), which removes adducts from the O6 position of guanine by accepting them onto a cysteine residue within its active site. Furthermore, fibroblasts and bone marrow cells of MGMT knockout mice are significantly more sensitive to the toxic effects of temozolomide than those from MGMT wild-type mice (2). The protective role of MGMT against the cytotoxic effect of temozolomide has been shown in human cell lines (3) and human xenograft models (4). MGMT can be inactivated by free guanine base derivatives that have alkyl groups at the O6 position, which act as pseudosubstrates.’’ O6-benzylguanine (5) and O6-(4-bromothenyl) guanine (PaTrin-2, Patrin, Lomeguatrib, KuDOS, Cambridge, United Kingdom; ref. 6) have been identified as the most promising MGMT inactivators. Compared with temozolomide used as a single agent, the combination
PaTrin-2-temozolomide has been shown to significantly increase tumor growth inhibition in human melanoma xenografts (7). "PaTrin-2 and O6-benzylguanine have recently entered phase I/II clinical trials.
DTIC+ Patrin-2 make the tumor cells more easily killed by Chemotherpy
I have spent the last 4 years collecting papers on this subject matter and piecing it together. You should see my hard drive. Paper/ powerpoints/ doctors email
I hope I can say I told you so in 10 to 20 years. Only time will tell.
I wish you well
Harry,
Did you have inflammation 15 days after I was infused with Anti-CTLA-4?
Well I did. It is a tell tale sign that I vaccinated myself with help of Anti-CTLA-4. Self vaccinated with my own Tumor-Specific Antigen. This very simular to Dr. Rosenburg's ACT therapy, but my was all in vivo. How long will it last, No one can say.
The graph is backed up with science.
for instance:
"Chemotherapy induces intratumoral expression of chemokines in cutaneous melanoma, favoring T cell infiltration and tumor control"
In conclusion, the present study identifies CXCR3 ligands and CCL5 as the main determinants of
T cell infiltration into cutaneous metastases and shows that chemotherapy, by inducing
expression of these chemokines within human tumors, may trigger T cell infiltration and tumor
control, resulting in prolonged patient survival. Therefore, screening for chemotherapeutic
products able to induce the expression of T cell attracting-chemokines in cancer cells may
identify drugs that improve the efficacy of immunotherapy
Corresponding author: Jean-Pierre Abastado, Laboratory of Tumour Immunology, Singapore
Immunology Network, 8A Biomedical Grove, #04-06 Immunos, Singapore 138648.
Tel: +65 6407 0003.
Fax: +65 6464 2057.
EM: abastado@immunol.a-star.edu.sg
Email Dr. Abastado for a copy of his paper.
————————————————————————————————————-
Sensitization of a human ovarian cancer cell line to
temozolomide by simultaneous attenuation of the
Bcl-2 antiapoptotic protein and DNA repair by
O6-alkylguanine-DNA alkyltransferase
Introduction
"Temozolomide and or DTIC is an alkylating agent that mediates its cytotoxic effect by forming O6-methylguanine (O6-meG)DNA adducts, which during DNA replication pair preferentially with thymidine. These O6-meG:T mispairs can result in a G-to-A point mutation during a subsequent round of DNA replication but are also substrates for the postreplication mismatch repair pathway, which
fter a further round of DNA replication leads to apoptosis (1). O6-meG DNA adducts can be repaired by the DNA repair protein O6-alkylguanine-DNA alkyltransferase (MGMT), which removes adducts from the O6 position of guanine by accepting them onto a cysteine residue within its active site. Furthermore, fibroblasts and bone marrow cells of MGMT knockout mice are significantly more sensitive to the toxic effects of temozolomide than those from MGMT wild-type mice (2). The protective role of MGMT against the cytotoxic effect of temozolomide has been shown in human cell lines (3) and human xenograft models (4). MGMT can be inactivated by free guanine base derivatives that have alkyl groups at the O6 position, which act as pseudosubstrates.’’ O6-benzylguanine (5) and O6-(4-bromothenyl) guanine (PaTrin-2, Patrin, Lomeguatrib, KuDOS, Cambridge, United Kingdom; ref. 6) have been identified as the most promising MGMT inactivators. Compared with temozolomide used as a single agent, the combination
PaTrin-2-temozolomide has been shown to significantly increase tumor growth inhibition in human melanoma xenografts (7). "PaTrin-2 and O6-benzylguanine have recently entered phase I/II clinical trials.
DTIC+ Patrin-2 make the tumor cells more easily killed by Chemotherpy
I have spent the last 4 years collecting papers on this subject matter and piecing it together. You should see my hard drive. Paper/ powerpoints/ doctors email
I hope I can say I told you so in 10 to 20 years. Only time will tell.
I wish you well
Harry,
Did you have inflammation 15 days after I was infused with Anti-CTLA-4?
Well I did. It is a tell tale sign that I vaccinated myself with help of Anti-CTLA-4. Self vaccinated with my own Tumor-Specific Antigen. This very simular to Dr. Rosenburg's ACT therapy, but my was all in vivo. How long will it last, No one can say.
The graph is backed up with science.
for instance:
"Chemotherapy induces intratumoral expression of chemokines in cutaneous melanoma, favoring T cell infiltration and tumor control"
In conclusion, the present study identifies CXCR3 ligands and CCL5 as the main determinants of
T cell infiltration into cutaneous metastases and shows that chemotherapy, by inducing
expression of these chemokines within human tumors, may trigger T cell infiltration and tumor
control, resulting in prolonged patient survival. Therefore, screening for chemotherapeutic
products able to induce the expression of T cell attracting-chemokines in cancer cells may
identify drugs that improve the efficacy of immunotherapy
Corresponding author: Jean-Pierre Abastado, Laboratory of Tumour Immunology, Singapore
Immunology Network, 8A Biomedical Grove, #04-06 Immunos, Singapore 138648.
Tel: +65 6407 0003.
Fax: +65 6464 2057.
EM: abastado@immunol.a-star.edu.sg
Email Dr. Abastado for a copy of his paper.
————————————————————————————————————-
Sensitization of a human ovarian cancer cell line to
temozolomide by simultaneous attenuation of the
Bcl-2 antiapoptotic protein and DNA repair by
O6-alkylguanine-DNA alkyltransferase
Introduction
"Temozolomide and or DTIC is an alkylating agent that mediates its cytotoxic effect by forming O6-methylguanine (O6-meG)DNA adducts, which during DNA replication pair preferentially with thymidine. These O6-meG:T mispairs can result in a G-to-A point mutation during a subsequent round of DNA replication but are also substrates for the postreplication mismatch repair pathway, which
fter a further round of DNA replication leads to apoptosis (1). O6-meG DNA adducts can be repaired by the DNA repair protein O6-alkylguanine-DNA alkyltransferase (MGMT), which removes adducts from the O6 position of guanine by accepting them onto a cysteine residue within its active site. Furthermore, fibroblasts and bone marrow cells of MGMT knockout mice are significantly more sensitive to the toxic effects of temozolomide than those from MGMT wild-type mice (2). The protective role of MGMT against the cytotoxic effect of temozolomide has been shown in human cell lines (3) and human xenograft models (4). MGMT can be inactivated by free guanine base derivatives that have alkyl groups at the O6 position, which act as pseudosubstrates.’’ O6-benzylguanine (5) and O6-(4-bromothenyl) guanine (PaTrin-2, Patrin, Lomeguatrib, KuDOS, Cambridge, United Kingdom; ref. 6) have been identified as the most promising MGMT inactivators. Compared with temozolomide used as a single agent, the combination
PaTrin-2-temozolomide has been shown to significantly increase tumor growth inhibition in human melanoma xenografts (7). "PaTrin-2 and O6-benzylguanine have recently entered phase I/II clinical trials.
DTIC+ Patrin-2 make the tumor cells more easily killed by Chemotherpy
I have spent the last 4 years collecting papers on this subject matter and piecing it together. You should see my hard drive. Paper/ powerpoints/ doctors email
I hope I can say I told you so in 10 to 20 years. Only time will tell.
I wish you well
Harry, I thinks the "Magic Bullet" will be a combinatorial therapy. It will most likely drugs strung in a sequence that :
1) A drug combo to make the tumor more susceptible to Chemo to shed Tumor-Specific antigens from dying tumor cells (DTIC,Patrin-2,Cisplatin,TMZ,radiation,biochemo..etc)
2) a drug combo to suppress the Tregs and help activate T-cells (Yervoy,Anti-PD-1, Anti-Gal-3 ..etc)
3) Finally a drug that keeps the T-cell (Cytotoxic T-lymphocytes) activated, functional and that is needed for survival.
Harry, I thinks the "Magic Bullet" will be a combinatorial therapy. It will most likely drugs strung in a sequence that :
1) A drug combo to make the tumor more susceptible to Chemo to shed Tumor-Specific antigens from dying tumor cells (DTIC,Patrin-2,Cisplatin,TMZ,radiation,biochemo..etc)
2) a drug combo to suppress the Tregs and help activate T-cells (Yervoy,Anti-PD-1, Anti-Gal-3 ..etc)
3) Finally a drug that keeps the T-cell (Cytotoxic T-lymphocytes) activated, functional and that is needed for survival.
"Ultimately, the research suggested that a combination of drugs blocking the PI3K, mTORC1/2 and MEK1/2 pathways represent the optimal combination for use with a BRAF inhibitor to mitigate the development of resistance. "
"All three compounds we used to overcome resistance to BRAF inhibition are already undergoing clinical evaluation. Therefore, we believe this particular combination approach represents a promising and translatable strategy for addressing BRAF inhibitor resistance in a subset of melanomas," Dr. Lo says.
"Among clinical trials currently enrolling melanoma patients with BRAF mutations are those combining BRAF and MEK inhibition and others combining PI3K/mTOR and MEK inhibition. Other highly-watched trials include those which combine a BRAF inhibitor with ipilimumab. "
Source: Dematology Times
