Novel method to treat diabetes - Hosein Kouros-Mehr

A recent report in Nature* describes a potentially new way of treating patients with type-2 diabetes.  The approach involves block an enzyme involved in the degradation of insulin, thereby boosting insulin levels.  The authors identify inhibitors of the insulin-degrading enzyme IDE.  A physiologically active IDE inhibitor was identified using a DNA-templated macrocycle small molecule library.  The inhibitor binds to IDE in a binding pocket located distally from the catalytic site.  Obese mice treated with the IDE inhibitor showed improved glucose tolerance upon administration of oral glucose.  Interestingly, the IDE inhibitor regulated multiple hormone levels in these mice, including glucagon and amylin, in addition to insulin.  This study suggests that inhibition of insulin degrading enzyme could be a novel approach for the treatment of diabetes.  

Maianti, et. al.  (2014).  Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones

Nature, doi:10.1038/nature13297

.Hosein Kouros-Mehr

Evidence of cancer stem cells in patient tumors - Hosein Kouros-Mehr

May 15, 2014

A recent paper* in Cancer Cell provides evidence of cancer stem cells in patient-derived tumors, which may validate the cancer stem cell hypothesis in a hematopoietic malignancy.  The cancer stem cell hypothesis has remained controversial due to experimental confounding variables, such as the strain of mice used for cancer stem cell implantation.  This study suggests that a rare population of Lin−CD34+CD38−CD90+CD45RA cells function as the propagating cells in patients with low- to intermediate-risk myelodysplastic syndrome.

Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by inefficient hematopoiesis and frequent progression to AML.  The authors of the study obtained MDS cells from patients and compared the relationships between  Lineage− (Lin−)CD34+CD38−CD90+CD45RA− candidate MDS-SCs with myeloid-restricted granulocyte-macrophage and megakaryocyte-erythroid progenitors (GMPs and MEPs).  They also transplanted the Lin−CD34+CD38−CD90+CD45RA− cells into mice and found that they gave rise to tumors with the same molecular signatures as those isolated directly from the patients.  The Lin−CD34+CD38−CD90+ MDS-SCs were molecularly and functionally distinct from clonally involved GMPs and MEPs and the Lin−CD34+CD38−CD90+ cells were able to replenish GMPs and MEPs, establishing their hierarchical relationship.

The authors found that deletion of 5q was among the first genetic lesions in MDS in the cancer stem cell population.  The 5q deletion was found to precede the acquisition of recurrent driver mutations in MDS , which served to confer self-renewal properties to MDS progenitors.

* Woll, et. al. (2014).  Myelodysplastic Syndromes Are Propagated by Rare and Distinct Human Cancer Stem Cells In Vivo.  Cancer Cell, in press

http://dx.doi.org/10.1016/j.ccr.2014.03.036

Hosein Kouros-Mehr

Novel immunotherapy approach - Hosein Kouros-Mehr

A recent paper* in Science reports that T cells recognizing a mutant protein found only in cancer cells can elicit an anti-tumor response when injected into a patient with end-stage epithelial cancer.  
The authors show that a 43-year old patient with metastatic cholangiocarcinoma carried tumor-infiltrating lymphocytes that recognized a mutant form of erbb2-interacting protein (ERBB2IP).  To do this, the authors resected lung metastases from the patient for whole exome sequencing and found 26 nonsynonymous mutations.  For each mutation, they created minigene constructs (containing the mutation and 12 flanking amino acids) and transfected constructs into antigen-presenting cells for co-culture with patient-derived tumor-infiltrating lymphocytes.  They found that  a patient-derived T-cell clone responded to mutant ERBB2IP and elicited a T-cell response with the release of IFN-gamma and activation of OX40 and 4-1BB.
The mutated ERBB2IP-specific T cells from the patient were then expanded and used for adoptive transfer to determine if these cells could elicit an anti-tumor response in the patient.  The patient received 42.4 billion tumor-infiltrating lymphocytes containing these T cell clones and also received 4 doses of IL-2 to enhance T-cell proliferation.  The patient displayed tumor regression 2 months after therapy, despite showing evidence of progressive disease prior to treatment.  The patient showed disease stabilization for 13 months after therapy, after which time she experienced disease progression in lungs but not liver.  
Further work will be necessary to validate this approach in cancer therapy.  T-cell adoptive transfer was previously shown to be a viable option for cancer patients, and the explosion of cancer mutation data from TCGA and other sources will offer new targets for cancer immunotherapy.

*Tran, et. al. (2014). Cancer Immunotherapy Based on Mutation-Specific CD4+ T Cells in a Patient with Epithelial Cancer. Science Vol. 344 no. 6184 pp. 641-645 DOI: 10.1126/science.1251102

Hosein Kouros-Mehr

Novel mechanism for cancer metastasis - Hosein Kouros-Mehr

Cancer Paper 4/23/14 Hosein Kouros-Mehr

Cancer-Secreted miR-105 Destroys Vascular Endothelial Barriers to Promote Metastasis

Zhou et. a., Cancer Cell, Volume 25, Issue 4, p501–515, 14 April 2014

A recent paper suggests a new mechanism for metastasis of cancer cells to distant organs.  Metastasis is a complex process consisting of a series of steps that a cancer cell must achieve to establish de novo cancers in distant organs.  One of the rate-limiting steps in metastasis is the extravasation and growth of disseminated cells that have reached the vasculature of the distant organ.  Here the disseminated cells face several barriers:  (1) extravasation across the microvasculature of the distant site, including migration through the endothelial cell layer and basement membrane; (2) survival in the new microenvironment of the distant organ; (3) evasion of the immune response in the distant organ.

Zhou et al. suggest that tumor cells can secrete microRNAs to assist them in the metastatic process.  Namely, they suggest that tumors cells can secrete miR-105 into their microenvironment, which targets the ZO-1 tight junction protein gene in endothelials at sites of tumor dissemination.  This allows downregulation of tight junction proteins in endothelial cells, which then allows cancer cells to extravasate into distant organs.  Interestingly, circulating miR-105 was found to predict metastasis in early-stage breast cancer patients.  

New targets/drugs for oncology have traditionally focused on signaling pathways required for primary tumor cell proliferation and growth.  While many new cancer drugs have come to market over the last few decades, the overall survival rate of cancer has not decreased as greatly as expected.  Metastasis is the primary cause of mortality and morbidity in cancer and new drugs that block metastasis may help increase cancer survival rates.

Hosein Kouros-Mehr 

Novel mutations discovered in a form of ovarian cancer Hosein Kouros-Mehr

A recent paper* in Nature Genetics discovered mutations in the SMARCA4 gene in a form of ovarian cancer known as small cell carcinoma of the ovary.  This cancer is highly aggressive and mostly affects young women.  The authors sequenced tumors from 12 patients and discovered loss of function mutations in SMARCA4 in 100% of the patients (probability of that happening by chance is less than 0.0000000000000002).  The importance of this finding is that it may lead to targeted therapies that can be tailored for patients with this disease.  

The SMARCA4 gene is an ATP-dependent helicase that is part of the SWI/SNF complex.  This complex regulates chromatin remodeling and is important for transcriptional activation of genes that may be normally silenced in heterochromatin.  SWI/SNF complex is composed of many proteins and its mechanism of action is largely unknown, but it is thought that SWI/SNF can destabilize histone-DNA interaction in an ATP-dependent manner and lead to chromatin remodeling of target genes, thereby altering the accessibility and transcription of the target genes.  SMARCA4 is a ATP-dependent helicase, which means it helps separate/unwind the strands of DNA using energy derived from ATP hydrolysis.  

The authors found that SMARCA4 mutations in these patients were all loss of function mutations that lead to significantly less SMARCA4 protein in the cells. Interestingly, the overexpression of SMARCA4 in SMARCA4-null cancer cell lines led to suppression of cell growth, suggesting that SMARCA4 is a bona fide tumor suppressor.  The depletion of SMACA4 using lentiviral shRNA knockdown led to increase cell growth in cell lines.  

SMARCA4 mutations are also found in bladder cance, stomach cancer, lung cancer, and glioma (5-8% frequency).  Most of these are missense mutations of uncertain consequence, though lung cancers contained frequent inactivating SMARCA4 mutations.  Further work will be necessary to identify candidate targets for drug discovery in SMARCA4 mutant tumors.  For example, the SMARCA2 ATPase may be upregulated in SMARCA4 mutant tumors and could be a candidate target in this patient population.  Further validation will be necessary to evaluate this potential new target.  

Jelinic, P., et. al.  (2014).  Recurrent SMARCA4 mutations in small cell carcinoma of the ovary.  

Nature Genetics

 

(2014) 

23 March 2014

Hosein Kouros-Mehr

the end of Tech Bubble 2.0? Hosein Kouros-Mehr

Is this the beginning of the end?

We are all familiar with the tech bubble of the late 1990s and crash in the early 2000s.  Could the charts be setting up for a similar tech crash this year?  While it is too early to tell, there are worrisome developments in technology stocks that could easily trigger a correction is not an outright crash over the next 12 months.  While this is a purely technical argument, the Nasdaq has not reached the highs of the 2000s and the animal spirits in today's market do not match those in the earlier bubble.  But it could be the memories of the first tech bubble crash that prevents the rise of the 2nd tech bubble today.

Here is the weekly Nasdaq-100 chart from 1998-2001.  Beginning in October 1998, the Nasdaq-100 spent 17 months above the 20 day weekly moving average and tested it 4 times during that time.  Then came a blow off top with a huge bearish engulfing candle that pierced the 20 day MA in March 2000.  It wasn't until 6 months later that it failed at the 50 day MA and began to crash to pre-rally levels.  The technical damage occurred swiftly and came as a surprise to many.  The wise ones took their money out during the period of consolidation before the crash.




Here is the Nasdaq-100 chart from the last two years. As in the previous chart, the Nasdaq-100 spent 15 months above the 20 day MA and tested it 4 times.  Over the last week it broke through the 20 day MA to the downside.  To continue the uptrend as it stands, the Nasdaq-100 will need to bounce quickly above the 20 day MA and while Janet Yellen may be the one who can do that, it appears that it's time to test the 50 day MA.  While it's too early to say whether "Tech Bubble 2.0" is truly over, caution is warranted in the near term.




Disclaimer:  The content of this blog should not be used as recommendation to purchase or sell securities.
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Hosein Kouros-Mehr

Cancer Archeology paper - Hosein Kouros-Mehr

Interesting article in Plos One describing discovery of metastastic carcioma in a young male who lived in Sudan in 1200 BC.  While not necessarily shedding light into the mechanisms of cancer metastasis, the paper presents interesting novel archeological data that can be used for future historical analyses.  The mechanisms that drive metastasis are likely to be as old as the mechanisms that drive normal development.  

RESEARCH ARTICLE

On the Antiquity of Cancer: Evidence for Metastatic Carcinoma in a Young Man from Ancient Nubia (c. 1200BC)

• Michaela Binder mail,
 
• Charlotte Roberts,
 
• Neal Spencer,
 
• Daniel Antoine,
 
• Caroline Cartwright

• Published: March 17, 2014
• DOI: 10.1371/journal.pone.0090924

• Article
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• Abstract
• Introduction
• Methods
• Results
• Discussion
• Conclusions
• Acknowledgments
• Author Contributions
• References

• Reader Comments (2)
• Media Coverage (2)
• Figures

Abstract

Cancer, one of the world’s leading causes of death today, remains almost absent relative to other pathological conditions, in the archaeological record, giving rise to the conclusion that the disease is mainly a product of modern living and increased longevity. This paper presents a male, young-adult individual from the archaeological site of Amara West in northern Sudan (c. 1200BC) displaying multiple, mainly osteolytic, lesions on the vertebrae, ribs, sternum, clavicles, scapulae, pelvis, and humeral and femoral heads. Following radiographic, microscopic and scanning electron microscopic (SEM) imaging of the lesions, and a consideration of differential diagnoses, a diagnosis of metastatic carcinoma secondary to an unknown soft tissue cancer is suggested. This represents the earliest complete example in the world of a human who suffered metastatic cancer to date. The study further draws its strength from modern analytical techniques applied to differential diagnoses and the fact that it is firmly rooted within a well-documented archaeological and historical context, thus providing new insights into the history and antiquity of the disease as well as its underlying causes and progression.

Hosein Kouros-Mehr