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It looks like substantially inhibiting the (re)activation of the stem cells of cancers is now possible by inhibiting the NOTCH pathways.

 

It was just done with leukemia in animals using a monoclonal antibody. The leukemia initiating cells did not survive. They were able, not only to get rid of cancerous cells, but also of the dormant stem cells starting it all.

 

I quote from the news release at UC San Diego:

Date: July 02, 2012 

Researchers Block Pathway to Cancer Cell Replication

NOTCH1 Signaling Promotes T-Cell Acute Lymphoblastic Leukemia-Initiating Cell Regeneration

Research suggests that patients with leukemia sometimes relapse because standard chemotherapy fails to kill the self-renewing leukemia initiating cells, often referred to as cancer stem cells.  In such cancers, the cells lie dormant for a time, only to later begin cloning, resulting in a return and metastasis of the disease.

One such type of cancer is called pediatric T cell acute lymphoblastic leukemia, or T-ALL, often found in children, who have few treatment options beyond chemotherapy.

A team of researchers – led by Catriona H. M. Jamieson, MD, PhD, associate professor of medicine at the University of California, San Diego School of Medicine and director of Stem Cell Research at UC San Diego Moores Cancer Center – studied these cells in mouse models that had been transplanted with human leukemia cells. They discovered that the leukemia initiating cells which clone, or replicate, themselves most robustly activate the NOTCH1 pathway, usually in the context of a mutation.

Earlier studies showed that as many as half of patients with T-ALL have mutations in the NOTCH1 pathway – an evolutionarily conserved developmental pathway used during differentiation of many cell and tissue types.  The new study shows that when NOTCH1 activation was inhibited in animal models using a monoclonal antibody, the leukemia initiating cells did not survive.  In addition, the antibody treatment significantly reduced a subset of these cancer stem cells (identified by the presence of specific markers, CD2 and CD7, on the cell surface).

“We were able to substantially reduce the potential of these cancer stem cells to self-renew,” said Jamieson.  “So we’re not just getting rid of cancerous cells: we’re getting to the root of their resistance to treatment – leukemic stem cells that lie dormant.”

The study results suggest that such therapy would also be effective in other types of cancer stem cells, such as those that cause breast cancer, that also rely on NOTCH1 for self-renewal. 

“Therapies based on monoclonal antibodies that inhibit NOTCH 1 are much more selective than using gamma-secretase inhibitors, which also block other essential cellular functions in addition to the NOTCH1 signaling pathway,” said contributor A. Thomas Look, MD of Dana-Farber/Children Hospital Cancer Center in Boston. “We are excited about the promise of  NOTCH1-specific antibodies to counter resistance to therapy in T-ALL and possibly additional types of cancer.”

In investigating the role of NOTCH1 activation in cancer cell cloning, the researchers showed that leukemia initiating cells possess enhanced survival and self-renewal potential in specific blood-cell, or hematopoietic, niches: the microenvironment of the body in which the cells live and self-renew.

The scientists studied the molecular characterization of CD34+ cells – a protein that shows expression in early hematopoietic cells and that facilitates cell migration – from a dozen T-ALL patient samples.

They found that mutations in NOTCH1 and other genes capable of promoting the survival of cancer stem cells co-existed in the CD34+ niche.  Mice transplanted with CD34-enriched NOTCH1 mutated T-ALL cells demonstrated significantly greater leukemic cloning potential than did mice without the NOTCH1 mutation.  The mutated cells were uniquely susceptible to targeted inhibition with a human monoclonal antibody, according to the scientists.

Additional contributors to the study include Wenxue Ma, Daniel J. Goff, Ifat Geron, Anil Sadarangani, Christina A. M. Jamieson, Angela C. Court, Alice Y. Shih, Qingfei Jiang, Christina C. Wu, Kristen M. Smith, Leslie A. Crews, Ida Deichaite, Sheldon R. Morris and Dennis A. Carson, UC San Diego Department of Medicine and Stem Cell Program, UC San Diego Moores Cancer Center; Alejandro Gutierrez, Dana-Farber/Children Hospital Cancer Center in Boston; and Kang Li, Ping Wei and Neil W. Gibson, Oncology Research Unit, Pfizer Global Research and Development, La Jolla Laboratories, San Diego."

 

Of course anyone with OM woudl be asking themselves if the NOTCH signaling pathways are also inportant in the proliferation of uveal melanoma (our cancer) stem cells. The answer is: YES! That was shown in a published study in February at Johns Hopkins. See http://www.ncbi.nlm.nih.gov/pubmed/22228632

 

It looks like our researchers are zooming in closer and closer to deal with the real culprits of many cancers. The specific cancer stem cells are the factories that need to be shut down.

 

Can't wait for the trials starting on the NOTCH inhibitors. Hopefully our doctors will catch on with this and start NOTCH inhibitor trials with uveal melanoma patients.

 

Maybe you guys could start asking questions about this with your doctors to make it visible for them? Can't hurt asking.

 

Peter L in NH

 

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edamaser's picture
Replies 2
Last reply 7/3/2012 - 9:39am
Replies by: paperdetective, RobC

Combination Small Molecule MEK and PI3K Inhibition Enhances Uveal Melanoma Cell Death in a Mutant GNAQ and GNA11 Dependent Manner

  1. Jahan S. Khalili1,
  2. Xiaoxing Yu1,
  3. Ji Wang2,
  4. Brendan C. Hayes1,
  5. Michael A. Davies3,
  6. Gregory Lizee4,
  7. Bita Esmaeli5, and
  8. Scott E. Woodman6,*

+ Author Affiliations


  1. 1Melanoma Medical Oncology, MD Anderson Cancer Center

  2. 2Thoracic and Cardiovascular surgery, MD Anderson cancer Center

  3. 3Melanoma Medical Oncology and Systems Biology, M. D. Anderson Cancer Center

  4. 4Melanoma Medical Oncology, M.D. Anderson Cancer Center

  5. 5Head and Neck Surgery, Section of Ophthalmology, MD Anderson Cancer Center

  6. 6Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center
  1. *Corresponding Author:
    Scott E. Woodman, Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, South Campus Research Building, SCR 2.3022, 7455 Fannin St., Houston, TX, 77054, United States swoodman@mdanderson.org
Abstract

Purpose: Activating-Q209L/P mutations in GNAQ or GNA11 (GNAQ/11) are present in ∼80% of uveal melanomas (UM). Mutant GNAQ/11 are not currently therapeutically targetable. Inhibiting key downstream effectors of GNAQ/11 represents a rational therapeutic approach for UMs that harbor these mutations. The MEK/MAPK and PI3K/AKT pathways are activated in UM. In this study, we test the effect of the clinically relevant small molecule inhibitors GSK1120212 (MEK inhibitor) and GSK2126458 (pan class I PI3K inhibitor) on UM cells with different GNAQ/11 mutations. Experimental Design: We use the largest set of genetically annotated uveal melanoma cell lines to-date to perform in vitro cellular signaling, cell cycle regulation, growth and apoptosis analyses. RNA interference and small molecule MEK and/or PI3K inhibitor treatment were employed to determine the dependency of cells with different GNAQ/11 mutation backgrounds on MEK/MAPK and/or PI3K/AKT signaling. Proteomic network analysis was performed to unveil signaling alterations in response to MEK and/or PI3K inhibition. Results: GNAQ/11 mutation status was not a determinant of whether cells would undergo cell cycle arrest or growth inhibition to MEK and/or PI3K inhibition. A reverse correlation was observed between MAPK and AKT phosphorylation after MEK or PI3K inhibition, respectively. Neither MEK nor PI3K inhibition alone was sufficient to induce apoptosis in the majority of cell lines; however, the combination of MEK + PI3K inhibitor treatment caused marked apoptosis in a GNAQ/11 mutant-dependent manner. Conclusions: MEK + PI3K inhibition may be an effective combination therapy in uveal melanoma given the inherent reciprocal activation of these pathways in UM.

  • Received December 14, 2011.
  • Revision received May 30, 2012.
  • Accepted June 1, 2012.
  • Copyright © 2012, American Association for Cancer Research. 

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ThatHomeschoolDad's picture
Replies 8
Last reply 6/26/2012 - 5:33pm

I'm not talking about studies -- that's another topic and then some.  I mean articles, online or print, that should be in the Welcome Basket for any new OM patient.  What must-reads have you found?  I'll start us off:

 

CURE Today article on super survivors, that is, "terminal" patients who are re-writing the odds.  Does not discuss OM, but useful anyway:

www.curetoday.com/index.cfm/fuseaction/article.show/id/2/article_id/1463

 

The Median Isn't the Message, the smartest, most thoughtful essay ever on statistics. A must for anyone Googling their disease.  Should be a laminated handout in every oncologist's office:

www.cancerguide.org/median_not_msg.htm

 

Postcards From Beyond the Zero, another great one from CancerGuide.org's Statistics section.  Actually, the whole Statistics section is a must-read:

www.cancerguide.org/postcardsfbz.html

Keep Rowing!

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Shelby - MRF's picture
Replies 1
Last reply 6/26/2012 - 5:29pm
Replies by: ThatHomeschoolDad

Posted on behalf of edamaser:

Delayed Systemic Recurrence of Uveal Melanoma
Kolandjian, Nathalie A. BA; Wei, Caimiao PhD; Patel, Sapna P. MD; Richard, Jessica L. ANP; Dett, Tina FNP; Papadopoulos, Nicholas E. MD; Bedikian, Agop Y. MDAbstract

Context: Metastatic uveal melanoma recurrence after >=10 years is not well studied in the clinical literature. This study describes the clinical characteristics and natural history of patients with delayed tumor recurrence.

Objective: To describe the characteristics of patients with delayed systemic recurrence of uveal melanoma and the natural history of the disease after recurrence.

Evidence Acquisition: This is a chart review of patients treated between 1994 and 2008 at The University of Texas, MD Anderson Cancer Center for uveal melanoma whose disease recurred >=10 years after treatment of the primary tumor.

Results: Of 463 patients treated for metastatic uveal melanoma, 305 developed systemic recurrence within 5 years from the time of diagnosis of primary melanoma, 97 developed systemic recurrences between 5 and 10 years, whereas 61 patients developed metastasis after >=10 years. The interval between primary to first systemic metastasis was a significant independent predictor of survival time from first systemic metastasis. The median survival time for patients with delayed metastatic recurrence after >=10 years was significantly longer than for patients who had intermediate or early systemic recurrence. Levels of lactate dehydrogenase, serum alkaline phosphatase, serum albumin, age, M-stage, and performance status at time of recurrence, as well as sex were also independent predictors of survival time from systemic recurrence.

Conclusions: Longer time interval between primary and first systemic metastasis is significantly correlated with prolonged survival. Patients who survive >=10 years without tumor metastasis after treatment for primary uveal melanoma cannot be considered cured. Prognosis remains poor for patients with metastatic uveal melanoma.

(C) 2012 Lippincott Williams & Wilkins, Inc. 

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On Sunday, August 12th, lace up your sneakers and join the Melanoma Foundation of New England at the starting line for the 2012 New Balance Falmouth Road Race. You can help spread awareness and educate others in the fight against melanoma.

Runners have been raising funds and awareness for the Melanoma Foundation of New England since 2004. Running for Cover, the Foundation's running team, has been running Falmouth for the past four years. We aim to raise more than $15,000 this year! Runner will be required to raise a minimum of $1,000 to help us reach our goal.

If you, or someone you know, is interested in joining Running for Cover, please visit our website, apply online, or email jshea@mfne.org.

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When you have been recently diagnosed with ocular melanoma, I believe there is nothing more inspirational to help one deal with it than Steve Job's (Apple's new deceased CEO) 2005 Stanford commencement speech, just after he was diagnosed with pancreatic cancer.

The video is heer http://www.youtube.com/watch?v=UF8uR6Z6KLc

The text is here http://facingcancertogether.witf.org/end-of-life/steve-jobs-inspirationa...

And if you want more inspiring details on Steve Jobs, I recommend the approved biography by Walter Isaacson.

 

Peter L in NH

diagnosed jan 2012, biopsied class 1b cells feb 2012,  proton beamed feb 2012, currently no mets, central vision on tumor eye virtually gone, vision in other (lazy) eye also part compromised

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ThatHomeschoolDad's picture
Replies 2
Last reply 6/23/2012 - 8:25am
Replies by: eyecancerny, RobC

What a great conference in Philly.  Now I'm all revved up!  Anyway...

For those of us who chatted afterward, and for anyone else who'd like the info, here some links I mentioned regarding talking to kids about cancer:

YouTube BBC animated series on the body -- Search for "Once upon a time in the body" or go to the member page of the one user who seems to have uploaded nearly the whole series -- www.youtube.com/user/isgota

 It is, as they say, absolutely brilliant.  Also free.

Brainpop.com -- Search on "cancer" and you'll get two or three good animated vids for kids.  You may have to sign up for the free trial to access it.  I’d post the vids, but they are embedded Flash.

I thought there might be one link for Gilda’s Club, but each chapter seems to have its own site, so you’ll have to Google based on your location.  The Wellness Community, which at least in NJ has merged with Gilda’s, does have a single national site, from which you can find local chapters:  www.cancersupportcommunity.org

We go to the parent / kids group Wellness runs in NJ, and it’s super.

The other resource to ask for at your local cancer center or hospital is a Child Life Specialist.   If she’s a Certified Play Therapist, all the better.  If not, try anyway.  If your hospital doesn't have one, look elsewhere.

Seriously, do it.

Monday would be good.

I'm still poking around for more.  Will post under this topic as acquired.

--Tom

Keep Rowing!

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margaretrogers57's picture
Replies 1
Last reply 6/19/2012 - 12:54pm
Replies by: paperdetective

Dear  Friends,

 

My husband has had ipi and gm-csf in trial.  Showed progression although small in some mm sized tumors.  We went to y-90 next.  2 1/2 months after rt. and a month after left lobe treated, tumors were significantly bigger.  Also some bone mets appeared. Talking about Temoolomide or azd6244 trial @ vanderbilt or pd-1 drug @ moffitt.  Anyone out there that has done these?  Thanks, margaret

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margaretrogers57's picture
Replies 1
Last reply 6/19/2012 - 10:04am
Replies by: ThatHomeschoolDad

Looking for trials of anti-pd-1.  Does anyone know of any that accept ocular primary and previous yervoy?  Tried Moffitt, but looking for something closer to TN.  All help is welcome.  Thanks, Margaret

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Looking for trials of anti-pd-1.  Does anyone know of any that accept ocular primary and previous yervoy?  Tried Moffitt, but looking for something closer to TN.  All help is welcome.  Thanks, Margaret

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ALM's picture
Replies 2
Last reply 6/17/2012 - 8:50pm
Replies by: tommonoli, ALM

Hi Everyone

From what I have read my melanoma is fairly rare. Acral Lentiginous Melanoma. Is there anyone out there who has the same disease and can offer me any info? I am stage 4. The primary liesion was on the middle toe which was amputated. A year later another liesion appeared on the ankle which was surgically excluded. I would like to know if ALM is any more dangerous or aggressive than other types of melanoma or are all melanoma basically the same?

Thanks for any help.

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Hi Friends, 

I am just posting this here because I am tryign to do whatever I can to spread the work. Amanda was a CrossFit competitor who lost her life in 2010 to Melanoma. CrossFit honored her by naming a workout after her, a workout that is actually quite difficult. 

I have started a memorial fundraiser in her name called The Amanda Miller Memorial Wod, www.amandawod.com, and I am simply trying to raise awareness. 

there is also a facebook page, www.facebook.com/amandawod, so if you know ANYONE who does crossfit, please pass this information along to them, encourage them to register, and participate. We are trying to raise $20,000 (I know, not a lot but every bit helps) to donate to Memorial Sloan Kettering Cancer Center in Amanda's name, specifically for melanoma research. 

Thank you 

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Heather's picture
Replies 6
Last reply 5/27/2012 - 2:10pm
Replies by: edamaser, tommonoli, Heather, lak

Hello, my name is Heather and I was diagnosed with ocular melanoma in 1995 at the age of 22. I have been very fortunate and have had no metastasis thus far. On my last CT of the chest two 3mm pulmonary nodules were found.  Upon re-evaluation of my scans the one was present on the previous years scan and showed no change....a good thing. I go next month for a follow up CT .  I am hopeful that this will turn out to be nothing, but as you all know it is scary. Until recently, I thought I was safe from metastasis since it had been so long(naive I guess).  After this most recent CT's results, I began to research and came across some people with very long gaps between initial diagnosis and metastasis. Just wondering if this is common? Thanks! Heather

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Nan in Nebraska's picture
Replies 8
Last reply 5/24/2012 - 11:14pm

Sara and Lesley, both of you being physicians, I'd like your opinions.

The results of my scans are not what I wanted to hear, but not surprising. The nodular mass between stomach and spleen is 5.2 x 3.6, up from 4.3 x 2.9 in Jan. and 3.4 x 2.3 in Oct., 2011. Several mesenteric/lymph nodes have also increased. Slight enlarged nodule in right lung base. (these have not really scared me as I've had numerous areas and they do seem to remain approx. the same) Ironically, radiologist feels some improvement in the liver as he only identified two locations, but MRI of abdomen in Jan. stated 5 lesions from Nebraska radiologist and 6 lesions from Dr. Sato?? I have sent my info. to Dr. Nutting for review. As I stated before, my main focus is the large lesion by the stomach. I asked the doctor that called yesterday (my doctor on vacation) about the possibility of doing Ipi re-induction, as that had been approved when I was on the compassionate trial, then doing cyberknife to the lesion after the Ipi (hopefully to get the same effect as the patient of Dr. Wolchoks) and his response was "how do you feel" -  "you know you could die from doing the Ipi". I told him I'd had very little if any side effects the first time and he said that it could be different the next time. I felt he was a bit negative! Do you have to wait to feel bad before you do something? I'm frustrated/confused.... I do feel fine. Do I just sit and let things GROW??

I did ask them to re-read my PET scan that was done in Jan. as the only mention was mild uptake in my one shoulder and I've been having some rotator cuff issues. Stated- PET images were "clear of any metabolically significant activity".

Something else I wanted to mention was that my LDH on my last labs was 95, which is below normal. Any thoughts on that?

I'm abit down, not knowing what the next step should be. I see my doctor on Monday, the 19th. She is very good and does listen, but is not a melanoma specialist.

Anxiously awaiting your thoughts.

Nan

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