Hi Robin,
Thanks for your question.
There is a relatively detailed discussion of the JQ1 research in this thread here in the forum:
https://myelomabeacon.org/forum/dr-bradner-s-research-on-jq1-t677.html
As you suggested in your posting, JQ2 is a compound related to JQ1.
We are not aware of any new publications, abstracts, or public announcements so far related to development of JQ2 as a myeloma therapy.
It might be best to continue further discussion of JQ1-related therapies in the thread mentioned above.
Forums
Re: Myeloma cancer stem cell-targeted therapies
I like this discussion as I read with much interest Dr. Matsui's work concerning MMSC identification and resistance to treatment. I was very interested in this when my wife was going through a transplant last year. It struck me as odd that we collected a variety of cells during harvest - relying only on the initial therapy within the body to purify the harvest. If progenitor cells could be identified, couldn't they also be separated from the cell collection - hopefully resulting in a better post-transplant remission?
Now we are a year post transplant, and I have different thoughts. It has been my impression that the idea of a progenitor path for myeloma is generally accepted. However, identifying and developing therapies that efficiently treat the progenitor cells may not necessarily lead to a successful treatment. Other issues not necessarily related to progenitor cells can frustrate a treatment.
It is my impression that the current understanding of resistance to treatment concerns (a) tenacious adhesion and depth of the diseased cell in an environment that prevents drug access, (b) a population of diseased cells that do not present a binding site for therapies, (c) rapid growth rate (gene deletion), or (d) some combination of any of these. From what I can gather, new therapies seem to be attempting to address these issues. Removing or treating progenitor cells should be step in the right direction - but these other issues seem to be receiving more attention in the literature.
Now we are a year post transplant, and I have different thoughts. It has been my impression that the idea of a progenitor path for myeloma is generally accepted. However, identifying and developing therapies that efficiently treat the progenitor cells may not necessarily lead to a successful treatment. Other issues not necessarily related to progenitor cells can frustrate a treatment.
It is my impression that the current understanding of resistance to treatment concerns (a) tenacious adhesion and depth of the diseased cell in an environment that prevents drug access, (b) a population of diseased cells that do not present a binding site for therapies, (c) rapid growth rate (gene deletion), or (d) some combination of any of these. From what I can gather, new therapies seem to be attempting to address these issues. Removing or treating progenitor cells should be step in the right direction - but these other issues seem to be receiving more attention in the literature.
Re: Myeloma cancer stem cell-targeted therapies
Hi,
What about 2 different articles that came out recently?
The first article is about targeting tumour-initiating cells with TRAIL Based Combination Therapy: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0035830
This second article is about a new drug strategy (an anti-cancer peptide) that targets resistant leukemia and lymphoma developed from the Dana-Farber Cancer Institute, and I wonder if it applies to myeloma: http://www.newswise.com/articles/new-drug-strategy-attacks-resistant-leukemia-and-lymphoma
My question for both articles is when and how myeloma patients will begin to start benefitting from any of this research.
Thanks.
What about 2 different articles that came out recently?
The first article is about targeting tumour-initiating cells with TRAIL Based Combination Therapy: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0035830
This second article is about a new drug strategy (an anti-cancer peptide) that targets resistant leukemia and lymphoma developed from the Dana-Farber Cancer Institute, and I wonder if it applies to myeloma: http://www.newswise.com/articles/new-drug-strategy-attacks-resistant-leukemia-and-lymphoma
My question for both articles is when and how myeloma patients will begin to start benefitting from any of this research.
Thanks.
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Guest1
Re: Myeloma cancer stem cell-targeted therapies
trobinson,
There have been attempts to purge Myeloma from Autografts but they have not shown any improvements.
"Despite significant tumor cell reduction, CD34+ selection does not reduce RR and increases the risk of severe post-transplant infections. There was also no difference in RR between patients in either arm who received grafts with detectable tumor cells and those receiving grafts with no detectable tumor cells, suggesting that reinfused tumor cells may not be the main cause of relapse after autologous transplant in myeloma."
http://www.haematologica.org/content/92/8/1083.abstract?ijkey=72cb8cd59a7e6e800909fad2c12eca4800951be6&keytype2=tf_ipsecsha
The closest thing to an Auto with a clean graft is a syngeneic (exact twin) transplant.
'Two large registry analyses have compared the results of syngeneic transplantation with Auto-SCT or Allo-SCT. Gahrton et al89 reported on 25 syngeneic recipients reported to the EBMT and Bashay et al90 reported on 43 subjects reported to the CIBMTR. The outcomes of syngeneic transplant recipients were superior in terms of lower incidence of relapse/progression, PFS and, for the EMBT patients, longer OS compared to Auto-SCT. A possible explanation for this observation would be the presence of a syngeneic GVM (as demonstrated in animal models, but has not been successfully reproduced in humans)91,92 or due to absence of contaminating myeloma cells in the donor graft. This latter explanation is not supported by purging results of Auto-SCT.93–96 These results also support the use of syngeneic stem-cell transplantation as consolidation therapy of an initial remission in patients who have identical twin donors."
http://jco.ascopubs.org/content/28/29/4521.full
Recent data shows that antibodies develop after syngeneic transplant that help explain the superior results of syngeneic over Auto.
"Targets of curative donor-derived graft-versus-myeloma (GVM) responses after allogeneic hematopoietic stem cell transplantation (HSCT) remain poorly defined, partly because immunity against minor histocompatibility Ags (mHAgs) complicates the elucidation of multiple myeloma (multiple myeloma)-specific targets. We hypothesized that syngeneic HSCT would facilitate the identification of GVM-associated Ags because donor immune responses in this setting should exclusively target unique tumor Ags in the absence of donor-host genetic disparities. Therefore, in the present study, we investigated the development of tumor immunity in an HLA-A0201(+) multiple myeloma patient who achieved durable remission after myeloablative syngeneic HSCT. Using high-density protein microarrays to screen post-HSCT plasma, we identified 6 Ags that elicited high-titer (1:5000-1:10 000) Abs that correlated with clinical tumor regression. Two Ags (DAPK2 and PIM1) had enriched expression in primary multiple myeloma tissues. Both elicited Ab responses in other multiple myeloma patients after chemotherapy or HSCT (11 and 6 of 32 patients for DAPK2 and PIM1, respectively). The index patient also developed specific CD8(+) T-cell responses to HLA-A2-restricted peptides derived from DAPK2 and PIM1. Peptide-specific T cells recognized HLA-A2(+) MM-derived cell lines and primary multiple myeloma tumor cells. Coordinated T- and B-cell immunity develops against MM-associated Ags after syngeneic HSCT. DAPK1 and PIM1 are promising target Ags for MM-directed immunotherapy."
http://www.ncbi.nlm.nih.gov/pubmed/22267603
Mark
There have been attempts to purge Myeloma from Autografts but they have not shown any improvements.
"Despite significant tumor cell reduction, CD34+ selection does not reduce RR and increases the risk of severe post-transplant infections. There was also no difference in RR between patients in either arm who received grafts with detectable tumor cells and those receiving grafts with no detectable tumor cells, suggesting that reinfused tumor cells may not be the main cause of relapse after autologous transplant in myeloma."
http://www.haematologica.org/content/92/8/1083.abstract?ijkey=72cb8cd59a7e6e800909fad2c12eca4800951be6&keytype2=tf_ipsecsha
The closest thing to an Auto with a clean graft is a syngeneic (exact twin) transplant.
'Two large registry analyses have compared the results of syngeneic transplantation with Auto-SCT or Allo-SCT. Gahrton et al89 reported on 25 syngeneic recipients reported to the EBMT and Bashay et al90 reported on 43 subjects reported to the CIBMTR. The outcomes of syngeneic transplant recipients were superior in terms of lower incidence of relapse/progression, PFS and, for the EMBT patients, longer OS compared to Auto-SCT. A possible explanation for this observation would be the presence of a syngeneic GVM (as demonstrated in animal models, but has not been successfully reproduced in humans)91,92 or due to absence of contaminating myeloma cells in the donor graft. This latter explanation is not supported by purging results of Auto-SCT.93–96 These results also support the use of syngeneic stem-cell transplantation as consolidation therapy of an initial remission in patients who have identical twin donors."
http://jco.ascopubs.org/content/28/29/4521.full
Recent data shows that antibodies develop after syngeneic transplant that help explain the superior results of syngeneic over Auto.
"Targets of curative donor-derived graft-versus-myeloma (GVM) responses after allogeneic hematopoietic stem cell transplantation (HSCT) remain poorly defined, partly because immunity against minor histocompatibility Ags (mHAgs) complicates the elucidation of multiple myeloma (multiple myeloma)-specific targets. We hypothesized that syngeneic HSCT would facilitate the identification of GVM-associated Ags because donor immune responses in this setting should exclusively target unique tumor Ags in the absence of donor-host genetic disparities. Therefore, in the present study, we investigated the development of tumor immunity in an HLA-A0201(+) multiple myeloma patient who achieved durable remission after myeloablative syngeneic HSCT. Using high-density protein microarrays to screen post-HSCT plasma, we identified 6 Ags that elicited high-titer (1:5000-1:10 000) Abs that correlated with clinical tumor regression. Two Ags (DAPK2 and PIM1) had enriched expression in primary multiple myeloma tissues. Both elicited Ab responses in other multiple myeloma patients after chemotherapy or HSCT (11 and 6 of 32 patients for DAPK2 and PIM1, respectively). The index patient also developed specific CD8(+) T-cell responses to HLA-A2-restricted peptides derived from DAPK2 and PIM1. Peptide-specific T cells recognized HLA-A2(+) MM-derived cell lines and primary multiple myeloma tumor cells. Coordinated T- and B-cell immunity develops against MM-associated Ags after syngeneic HSCT. DAPK1 and PIM1 are promising target Ags for MM-directed immunotherapy."
http://www.ncbi.nlm.nih.gov/pubmed/22267603
Mark
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Mark
14 posts
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