An extremely rare and "almost always" fatal midline carcinoma effects just 20-40 individuals per year and there are about 200 people with this cancer in the US. It typically originates in the "midline" regions of the body, such as nose, mouth and sinuses in the head; trachea in the neck; upper airways, chest and thymus in the mediastinum. It effects children and adults, alike.
Since midline carcinoma cells are undifferentiated or poorly differentiated, this cancer is often misdiagnosed or undiagnosed. Diagnosis occurs upon chromosomal analysis and a discovery of a chromosomal rearrangement fusing a gene called NUT to a bromodomain gene BRD4.
Since midline carcinoma cells are undifferentiated or poorly differentiated, this cancer is often misdiagnosed or undiagnosed. Diagnosis occurs upon chromosomal analysis and a discovery of a chromosomal rearrangement fusing a gene called NUT to a bromodomain gene BRD4.
There is no cure!
This cancer is driven by a class of nuclear proteins called bromodomain proteins. For a very very long time, these proteins were considered undruggable targets--i.e., chemically impossible to target with drugs. Other undruggable targets are mutant P53, MIC and RAS proteins--the cancer drivers discovered about a half century ago to be responsible for over half of all cancers.
A May 2011 TED Boston talk by Jay Bradner of Dana Farber Institute, Boston, provides hope that such undruggable targets are not the holy cows, and we can find Achilles heels (or hoofs). To achieve this seemingly unsurmountable feat, Jay followed the research practices that are half a century old (but, often ignored or shunned these days,) which is to liberally share his findings, methods and prototype drugs with anyone who asked, the practice he said he borrowed from the software industry, opensource and crowdsource. As a result, he and the clinical world saw a discovery of a prototype drug JQ1 targeting the midline carcinoma target BRD4 protein. This has opened the possibility of developing a potential treatment for mildline carcinoma; a follow-up compound JQ2 is soon entering clinical trails, says Bradner in his TED talk.
Bromodomain-containing proteins
There are six families of bromodomain-containing proteins. One of these families called BET has a role in various cancers; BET family has four members, bromodomain containing 1 (BRD1), BRD2, BRD3 and BRD4 proteins. The activation of BRD4 drives midline carcinoma. The translocation of BRD4 gene with another gene called NUT (short for nuclear protein of the testis) results in a chimera which is essentially an "always-on" BRD4 capable of driving cancer. Midline carcinoma is often refered to as NUT midline carcinoma.
This cancer is driven by a class of nuclear proteins called bromodomain proteins. For a very very long time, these proteins were considered undruggable targets--i.e., chemically impossible to target with drugs. Other undruggable targets are mutant P53, MIC and RAS proteins--the cancer drivers discovered about a half century ago to be responsible for over half of all cancers.
A May 2011 TED Boston talk by Jay Bradner of Dana Farber Institute, Boston, provides hope that such undruggable targets are not the holy cows, and we can find Achilles heels (or hoofs). To achieve this seemingly unsurmountable feat, Jay followed the research practices that are half a century old (but, often ignored or shunned these days,) which is to liberally share his findings, methods and prototype drugs with anyone who asked, the practice he said he borrowed from the software industry, opensource and crowdsource. As a result, he and the clinical world saw a discovery of a prototype drug JQ1 targeting the midline carcinoma target BRD4 protein. This has opened the possibility of developing a potential treatment for mildline carcinoma; a follow-up compound JQ2 is soon entering clinical trails, says Bradner in his TED talk.
Bromodomain-containing proteins
There are six families of bromodomain-containing proteins. One of these families called BET has a role in various cancers; BET family has four members, bromodomain containing 1 (BRD1), BRD2, BRD3 and BRD4 proteins. The activation of BRD4 drives midline carcinoma. The translocation of BRD4 gene with another gene called NUT (short for nuclear protein of the testis) results in a chimera which is essentially an "always-on" BRD4 capable of driving cancer. Midline carcinoma is often refered to as NUT midline carcinoma.
How does BRD4 drive cancer?
Cancer cell or any other cell in the body share the same genome, but differs from what genes are on or off. The ON/OFF decisions are driven by the chemical (acetylation) tags on histone proteins coating the genes. The code of such tags (also called epigenetics) is maintained by histone acetyltransferases (HATs) and histone deacetylases (HDACs). And, bromodomain proteins monitor or manage HATs and HDACs activities. In the end, it is the bromodomain proteins which tell the cell to live and die as as liver cell or a cancer cell, regardless of how many times it divides and how many baby cells it creates through division. If only we could turn off a rouge BRD4 protein, we could reverse the identity of a cancer cell.
Cancer cell or any other cell in the body share the same genome, but differs from what genes are on or off. The ON/OFF decisions are driven by the chemical (acetylation) tags on histone proteins coating the genes. The code of such tags (also called epigenetics) is maintained by histone acetyltransferases (HATs) and histone deacetylases (HDACs). And, bromodomain proteins monitor or manage HATs and HDACs activities. In the end, it is the bromodomain proteins which tell the cell to live and die as as liver cell or a cancer cell, regardless of how many times it divides and how many baby cells it creates through division. If only we could turn off a rouge BRD4 protein, we could reverse the identity of a cancer cell.
JQ1 converts cancer cells into normal cells
Jay and a chemist, Jun Qi developed JQ1, a specific inhibitor of BRD4, which was named for Jun Qi's initials, at Dana Farber. Adding JQ1 to BRD4-addicted cancer cells in a test tube changed them to normal cells which was a wonderful finding! Cancer was reversible. But, Jay needed an animal model to prove drug's effect and show that it was non-toxic before being able to help patients. There is no animal model for midline carcinoma. Fortunately, he came across a young man from Connecticut literally dying from this cancer: The cancer filled his left lung, and this young man had a tube draining the cancer debris out of his lung (and that's all the doctors could do to make his end journey bearable.) Jay Bradner asked if he could use some of these drained cancer cells to test the drug, the young man agreed. Jay's team implanted these BRD4-addicted cancer cells in mice hind legs where huge tumors developed and mice died, except if the mice were treated with JQ1. JQ1 treated mice were cured and had no cancer. He then shared the drug, synthesis methods and all research with 40 labs in the US and 30 labs in Europe. The result was a tsunami of information in a very short time. New findings came pouring in. JQ1 could "normalize" a wide variety of cells: Leukemia cells became normal white cells and fatty liver became normal liver in mice.
Bringing drug to the patients
JQ1 does not have the best pharmacokinetics to reach clinical practice. There may also be patent issues. Joanne Kotz writes in SciBx, Oct 21, 2010, issue,
"The researchers didn't have to start from scratch. Instead, they designed the lead inhibitor, JQ1, based on information in the scientific literature and a patent held by Mitsubishi Tanabe Pharma Corp. covering thienodiazepines that bind to BRD4."However, Bradner's group has come up with a follow-on compound called JQ2. This drug is entering clinical trials in midline carcinoma, lymphoma of skin and multiple myeloma patients. The clinical development is being done by a company called Tensha Therapeutics, Cambridge, Mass., which was founded by James Bradner in July 2011.
Tensha Therapeutics is developing small molecule bromodomain inhibitors, a new class of epigenetic modulators of gene expression, to treat cancer and other serious disorders.
The company's programs are based on the discovery from the laboratory of Dr. James Bradner at the Dana-Farber Cancer Institute of first-in-class potent small molecule BET bromodomain inhibitors. The company's lead program is aimed at the treatment of patients with BRD4-NUT midline carcinoma, acute myeloid leukemias, multiple myeloma, and other diseases. Tensha is a Focused Company funded by HealthCare Ventures.
The success of JQ1 has spawned interest across the industry. HDAC inhibitors, in development for other cancers, are starting to look attractive as midline carcinoma treatments. Three such drugs are:
- Panobinostat (LBH589; Novartis, Switzerland) is an experimental drug.
- Romidepsin (Istodax; Celgene, N.J.) is FDA approved for cutaneous T-cell lymphoma.
- Vorinostat (Zolinza; Merck, Whitehouse Station, N.J.) is FDA approvedfor cutaneous T-cell lymphoma.
- additional list of HDAC inhibitors in clinical trails can be found here.
Other links and information
NUT Midline Carcinoma Registry (based at Brigham and Women's Hospital) http://www.nmcregistry.org/
Drugs' links:
Panobinostat:
MedlinePlus, Drugs.com, Company website , Wikipedia
Romidepsin:
PubMed
Health, Drugs.com,
Company website, Wikipedia
Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, Morse EM, Keates T, Hickman TT, Felletar I, Philpott M, Munro S, McKeown MR, Wang Y, Christie AL, West N, Cameron MJ, Schwartz B, Heightman TD, La Thangue N, French CA, Wiest O, Kung AL, Knapp S, & Bradner JE (2010). Selective inhibition of BET bromodomains. Nature, 468 (7327), 1067-73 PMID: 20871596
Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H, Sison EA, Magoon D, Qi J, Blatt K, Wunderlich M, Taylor MJ, Johns C, Chicas A, Mulloy JC, Kogan SC, Brown P, Valent P, Bradner JE, Lowe SW, & Vakoc CR (2011). RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature, 478 (7370), 524-8 PMID: 21814200
Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, Kastritis E, Gilpatrick T, Paranal RM, Qi J, Chesi M, Schinzel AC, McKeown MR, Heffernan TP, Vakoc CR, Bergsagel PL, Ghobrial IM, Richardson PG, Young RA, Hahn WC, Anderson KC, Kung AL, Bradner JE, & Mitsiades CS (2011). BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell, 146 (6), 904-17 PMID: 21889194
French CA (2010). NUT midline carcinoma. Cancer genetics and cytogenetics, 203 (1), 16-20 PMID: 20951314
Joanne Kotz. BET-ting on bromodomains. SciBX 3(41); doi:10.1038/scibx.2010.1224 | FullText |
No that is not true. It is possible to cure due to modern science that develop cure for cancer.
ReplyDeleteAjay,
ReplyDeleteI really enjoy your blog, Mission Tumor, and in especially, your post on December 11, 2011: “Midline Carcinoma Cancer Without a Cure: No More”. I feel strongly that this “almost always” fatal and extremely rare midline carcinoma is highly under reported. While researching this cancer, I found that according to the Journal of Clinical Oncology from the American Society of Clinical Oncology, patients typically live an average of 47 years, however survival time is less than a year after diagnosis. The average person in the United States lives to be 78, according to the Centers for Disease Control.
This cancer is lethal, rare and unpredictable (as midline carcinomas are not specific to any tissue or organ) and I feel there should be stronger advocacy and public awareness of prototype drugs JQ1 and JQ2. The greater the awareness, the greater the chances of survival for these patients.
I thought you might find the following video clip about the Methotrexate shortage interesting. I hope you will embed it into your blog and maybe in the future, we could swap blog roll links and widgets.
http://www.newsy.com/videos/children-s-leukemia-drug-supply-dangerously-low/
The clip does a great job of concisely sourcing and compiling news reports to emphasize the scope and context the content is being reported on. Newsy synthesizes and analyzes news into neutral comprehensive video clips showing a variety of opinions on the same topic.
I really appreciate your input, time and consideration.
Thank you,
Lyndsey Garza
lyndseyg@newsy.com
Lyndsey,
DeleteThank you for your comment. In drug discovery and development, you have to look beyond prototypes, i.e., JQ1 and JQ2. These prototypes have provided strong scientific rationale and brought in more candidates (such as, HDAC inhibitors) towards clinical testing in midline carcinoma. This is important because tumors generally develop resistance to targeted drugs, and patients need second and third options.
Could you please share the reference for Journal of clinical Oncology about survival statistics. Thank you.
Ajay
Ajay
ReplyDeleteI have a friend who was recently diagnosed with this awful cancer. He is only 30 and the tumor is on his jaw invading his entire mouth cavity. He cant eat or barely breathe. I wished they could of given him these drugs to help him.He was misdiagnosed in January and only recently (end of june) did the doctors decide this was the culprit. He is in hospice in illinois and survial is not an option we are told. It is in his bones and liver. He is suffering and has lost most of his body weight. Isnt there anyway to get a hold of the JQ1 and JQ2?
Thank you
Angela
Angela,
DeleteThere is one study sponsored by GlaxoSmithKline which is recruiting midline carcinoma patients:
A Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of GSK525762 in Subjects With NUT Midline Carcinoma (NMC)
ClinicalTrials.gov Identifier: NCT01587703
Drug: GSK525762
GSK's drug is in the same category as JQ1. They both target BET.
About GSK525762 from NCI website: "A small molecule inhibitor of the BET (Bromodomain and Extra-Terminal) family of bromodomain-containing proteins with potential antineoplastic activity. Upon administration, the BET inhibitor GSK525762 binds to the acetylated lysine recognition motifs on the bromodomain of BET proteins, thereby preventing the interaction between the BET proteins and acetylated histone peptides. This disrupts chromatin remodeling and gene expression. Prevention of the expression of certain growth-promoting genes may lead to an inhibition of tumor cell growth." NCI link: http://www.cancer.gov/drugdictionary?cdrid=733799
I'm not sure if JQ2 has entered clinical trials yet (JQ1 is not ideal for human use).
I would also suggest that your friend also look into HDAC inhibitors which are being tested for other indications, but may work for midline carcinoma (read above). Some of these HDAC inhibitors are already in clinic and many others are in clinical trials.
To search for HDAC inhibitors currently in trials go to http://clinicaltrials.gov/ct2/search/advanced and enter HDAC under "interventions" or click here
Good luck.
Ajay
DeleteThank you so much for the information I wished I would of gotten the name of what he had sooner but honestly didnt get diagnosis till end of June.
I think he is to far gone for anything honestly he has lost 150lbs and the tumor is actually coming out of his mouth and he can barely breathe or swallow and they cant even get a tube in to help him.
They are not doing anything at this point but Morephine.
Angela
Angela,
DeleteBesides fighting cancer and doing whatever you can, dying with dignity and without suffering is equally, maybe more, important.
God Bless your friend.
Ajay
ReplyDeletethank you for the information,I fear it is to late.Its unfortunate that they mis-diagnosed him a few times and he actually went 12 weeks total without any chemo or radiation while everyone tried to transfer records etc.. Eric cannot even swallow, the tumor is coming out of his mouth and they cannot get a tube in to assist in breathing or eating. They basically have him on morephine right now to keep him comfortable.They are not giving him any nourishment to sustain life. Its all very sad and we did not get this NMC diagnosis until end of June and still waiting on the latest biopsy.
thanks again for your time
Angela
Hi Ajay,
ReplyDeleteJust curious where you got the number that there are about 200 cases of NUT midline carcinoma in the US? i spoke to one of the Doctors who discovered the pathogenesis of this cancer and he said to date, he only knows of 98 cases reported in literates and reports -- world wide.
Thanks!
Ryan
Hi Ryan,
DeleteI believe, the number 98 (patients) is quoted from the following publication:
Midline carcinoma of children and young adults with NUT rearrangement.
French CA et al. J Clin Oncol. 2004 Oct 15;22(20):4135-4139. http://jco.ascopubs.org/content/22/20/4135.long
Actually 98 is not the number of midline carcinoma patients but number of patients with carcinoma who were tested for NUT and BRD4 gene rearrangements. These researchers found only 11 with NUT gene arrangements.
--
Another recent publication lists 22 NUT midline carcinoma cases. Read here:
NUT Midline Carcinoma. By Christopher Alexander French. Cancer Genet Cytogenet. 2010 November; 203(1): 16–20. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3000636/
---
Total of 200 patients is an estimate which I read in one of the publications. As soon as I find out which one was it, I will list it here. Note that the true incidence is unknown since this is a rare cancer.
Thanks,
Ajay