Replies to post #155200 on Biotech Values

[caravon]

Dear Peter,
Once more, thank you for the reply.

What frustrates me is absence of understanding and/or conviction in dealing with cancers. It appears that drugs do shrink tumors and extent survival but somehow it does not contribute much to an overall victory over major solid tumors.

[goodJohnhunting]

Biomavin,

Quote:
"Kinase inhibitors are currently the best we have in terms of treating cancer. A drug like Gleevec and the 2nd/3rd gen follow-ons have transformed a uniformly fatal disease into a chronic one, where patients now have a relatively normal life expectancy.

Right now we don't have any drugs that target cancer stem cells. By their very nature, stem cells are hardier than differentiated cells, and they don't multiply quickly, so standard chemo doesn't work on them either. There is also a needle in a haystack problem - cancer stem cells make up only a very small proportion of tumor cells.

And just as its hard to target cancer cells without also destroying regular cells, it will be hard to target cancer stem cells without also destroying your own normal stem cells. "

Imatinib has been a trail blazing drug and If my memory serves correct, was discovered by Nick Lydon. Novartis was lucky to have such a brilliant chemist.

Regarding "destroying normal cells". One reason we are seeing improved therapeutic effects of chemotherapy in combination with Bavituximab, is partially attributed to inhancement of "fractional kill", and the interruption of tumor cell cycle. A mitotic disruption, so to speak, and heard here first.

Sincerely,
John

[biocqr]

Listening to the Resverlogix presentation today, their BET (bromodomain) inhibitor platform was discussed as a potential cancer therapy.

I have minimal scientific background but did a little digging. I'm curious what others here think of this...

One elusive but promising target, (James) Watson said, is a protein in cells called Myc. It controls more than 1,000 other molecules inside cells, including many involved in cancer. Studies suggest that turning off Myc causes cancer cells to self-destruct in a process called apoptosis.

"The notion that targeting Myc will cure cancer has been around for a long time," said cancer biologist Hans-Guido Wendel of Sloan-Kettering. "Blocking production of Myc is an interesting line of investigation. I think there's promise in that."

Read more: http://www.foxnews.com/health/2013/01/09/dna-pioneer-james-watson-takes-aim-at-cancer-establishments/#ixzz2HdLN2pqM

BET inhibitors exhibit anticancer effects in both in vitro and
in vivo models of midline carcinoma (8), a rare but lethal disease
that frequently harbors a chromosomal translocation in which
the bromodomains of BRD4 are fused to the NUT gene (9).
Although other genetic abnormalities of BET family members in
cancer have not been described, we speculated that BET-bromodomain
inhibition may have broader utility as an anticancer
agent because BRD2, BRD3, and BRD4 are functionally linked
to pathways important for cellular viability and cancer signaling.

Expression of MYC was reduced by BET inhibitors within 1 h
after treatment (Fig. 4A), suggesting that BET proteins might be
exerting direct effects on the MYC locus.

http://www.pnas.org/content/early/2011/09/20/1108190108.full.pdf

A third variety of epigenetic proteins -- potentially the most appealing as therapeutic targets, because they switch genes on or off by "reading" the bookmarks -- has received scant scientific attention. Bradner and his colleagues turned to this little-explored corner of biology by focusing on NMC cells.
The disease is caused by a chromosomal "translocation," in which two genes from different chromosomes become connected and give rise to an abnormal, fused protein known as BRD4-NUT. A review of the scientific literature suggested that some members of the benzodiazepine family of drugs, which includes Valium, Xanax and Ativan, are active against "bromodomain" proteins such as BRD4. With that as a clue, Bradner and his Dana-Farber colleague Jun Qi, PhD, created an array of molecules to see if any inhibited a "reader" protein of the BRD4-NUT gene. One did, quite convincingly -- a hybrid molecule, which researchers named JQ1, for Qi.
The investigators worked with researchers in the U.S. and overseas to learn more about the properties of JQ1 and how it works in cells. Stefan Knapp, PhD, of Oxford University in England, provided crystal-clear images of the molecule bound to a protein; Olaf Wiest, PhD, of the University of Notre Dame, showed that the molecule is less flexible in the presence of a protein, explaining why it so effectively blocks the protein; and Andrew Kung, MD, PhD, of Dana-Farber, engineered animal models in which the molecule could be tested against NMC tumors.
The animal studies were especially encouraging. Investigators transplanted NMC cells from patients into laboratory mice, which were then given the JQ1 molecule.
"The activity of the molecule was remarkable," says Bradner, who is also an associate member of the Chemical Biology Program at the Broad Institute of Harvard and MIT. "All the mice that received JQ1 lived; all that did not, died."

http://www.sciencedaily.com/releases/2010/09/100924134953.htm

BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc

Highlights
BET bromodomain proteins regulate MYC transcription
The BET bromodomain inhibitor JQ1 selectively downregulates MYC and Myc-dependent target genes
BRD4 binds to IgH enhancers next to MYC in rearranged multiple myeloma cells
JQ1 inhibits myeloma cell proliferation in clinically relevant models

http://www.cell.com/abstract/S0092-8674(11)00943-3

Resverlogix
Our oncology program builds upon the recent discovery that BET inhibitors may have therapeutic potential in certain human cancers, and might lead to a class of more effective oncology drugs. The growth of multiple hematological cancers and solid tumors is driven by increased production of c-myc, a well-known oncogene that has been studied for more than 30 years. Despite the critical function this oncogene has in the development of cancer, treatments that target its activity have eluded discovery. Recent research has shown that BET inhibition results in the suppression of the activity of the c-myc gene in certain cancer cell types and the resulting loss of c-myc protein leads to inhibition of tumor cell proliferation. We have demonstrated that several of our compounds inhibit the proliferation of tumor cells derived from acute myelogenous leukemia (“AML”) and multiple myeloma (“MM”) and select solid tumors, suggesting significant potential. Multiple compounds are also active in an animal model of cancer. Based on these observations, we have an active drug discovery program to find and develop new, orally active compounds that work through inhibition of BET proteins and we are exploring approaches to identify the best patients to target based on a more robust understanding of the mechanisms driving responses to current treatment regimen.

http://www.resverlogix.com/programs/epigenetics/cancer.html