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Acute Lymphoblastic Leukemia (ALL) and Nanotechnology

Posted in Biomarkers & Medical Diagnostics, BioSimilars, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Prevention: Research & Programs, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Genome Biology, Nanotechnology for Drug Delivery, Population Health Management, Genetics & Pharmaceutical, tagged Acute Lymphoblastic Leukemia (ALL), B-cell, BCR-ABL, c-myc, Dox=NPs, Gene translocation, Hematopoiesis, Hematopoietic stem cells, JAK3 tyrosine kinase, MLL-AF4, nanotechnology, NOTCH1, T cells, TEL-AML, WHI-P131 on March 21, 2013| 2 Comments »

Author: Tilda Barliya PhD

Acute lymphoblastic leukemia (ALL), a malignant disorder of lymphoid progenitor cells, aﬀects both children and adults,
with peak prevalence between the ages of 2 and 5 years (2). Acute lymphocytic leukemia (ALL) is a heterogeneous disease, both in terms of its pathology and the populations that it affects. Disease pathogenesis involves a number of deregulated pathways controlling cell proliferation, differentiation, and survival that are important determinants of treatment response (3). Approximately 5200 new cases of ALL are estimated to have occurred in the United States in 2007 and survival varies with age and disease biology (3). Although five-year survival rates for ALL approach 90 percent with available chemotherapy treatments, the harmful side effects of the drugs, including secondary cancers and fertility, cognitive, hearing, and developmental problems, present significant concern for survivors and their families.

Biological and Clinical Prognostic Factors in ALL: Setting the Stage for Risk-Adapted Therapy

Of the many variables that influence prognosis the genetic subsets, initial white blood cell count (WBC), age at diagnosis, and early treatment response are the most important.

Childhood Acute Lymphoblastic Leukemia

Pathobiology

Acute lymphoblastic leukaemia is thought to originate from various important genetic lesions in blood-progenitor cells that are committed to diﬀerentiate in the T-cell or B-cell pathway, including mutations that impart the capacity for unlimited self-renewal and those that lead to precise stage-speciﬁc developmental arrest. In some cases, the first mutation along the multistep pathway to overt acute lymphoblastic leukaemia might arise in a haemopoietic stem cell possessing multilineage developmental capacity.

The dominant theme of contemporary research in pathobiology of acute lymphoblastic leukaemia is to understand the outcomes of frequently arising genetic lesions, in terms of their eﬀects on cell proliferation, diﬀerentiation, and survival, and then to devise selectively targeted treatments against the altered gene products to which the leukaemic clones have become addicted (2).

Prognostic factors used in pediatric and adult clinical trials

The Table illustrates the different prognostic factors in children and adults that may be used for risk stratification in current clinical trials (3).

Genetics

Chromosomal translocations that activate speciﬁ c genes
are a deﬁ ning characteristic of human leukaemias and
of acute lymphoblastic leukaemia in particular.
About 25% of cases of B-cell precursor acute lymphoblastic leukaemia, the most frequent form of acute leukaemia in children, harbour the TEL-AML1 fusion gene—generated by the t(12;21)(p13;q22) chromosomal translocation.

The presence of the TEL-AML1 fusion
protein in B-cell progenitors seems to lead to disordered
early B-lineage lymphocyte development, a hallmark of
leukaemic lymphoblasts.

Analysis of TEL-AML1-induced cord blood cells suggests that the fusion gene serves as a ﬁrst-hit mutation by endowing the preleukemic cell with altered self-renewal and survival properties.

In adults, the most frequent chromosomal translocation is t(9;22), or the Philadelphia chromosome, which causes fusion of the BCR signalling protein to the ABL non-receptor tyrosine kinase, resulting in constitutive tyrosine kinase activity and complex interactions of this fusion protein with many other transforming elements. BCR-ABL oﬀ ers an attractive therapeutic target, and imatinib mesilate, a small-molecule inhibitor of the ABL kinase, has proven eﬀective against leukaemias that express BCR-ABL
More than 50% of cases of T-cell acute lymphoblastic leukaemia have activating mutations that involve NOTCH1. NOTCH1, which translocates to the nucleus and regulates by transcription a diverse set of responder genes, including the MYC oncogene. The precise mechanisms by which aberrant NOTCH signalling (due to mutational activation) causes T-cell acute lymphoblastic leukaemia are still unclear but probably entail constitutive expression of oncogenic responder genes, such as MYC, and cooperation with other signalling pathways (pre-TCR [T-cell receptor for antigen] and RAS, for example). Interference with NOTCH signalling by small-molecule inhibition of γ-secretase activity has the potential to induce remission of T-cell acute lymphoblastic leukemia.

Additionally A recent discussion has aimed to reveal the genetic origin of the disease (1). Several of these genes, including ARID5B, IKZF1, and CEBPE, have been implicated in processes such as hematopoietic differentiation and development of ALL. These gene obviously adds up to a number of other gene mutations and translocation already discovered and are associated with disease progression (2) “The fact that alterations in these genes lead to ALL raises the question of what would happen if we restore these pathways in ALL and also make them possible exciting therapeutic targets as well.”

Nanotechnology and therapeutic

Dr. Rajasekaran, director and head of the Membrane Biology Laboratory University of Delaware, says that there are currently seven or eight drugs that are used for chemotherapy to treat leukemia in children. They are all toxic and do their job by killing rapidly dividing cells. these drugs don’t differentiate cancer cells from other healthy cells. “The good news is that these drugs are 80 to 90 percent effective in curing leukemia. The bad news is that many chemotherapeutic treatments cause severe side effects, especially in children. In preclinical models of leukemia, Dr. Rajasekaran research team have created NP with an average diameter of 110 nm were assembled from an amphiphilic block copolymer of poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL) bearing pendant cyclic ketals (ECT2). The researches have been encapsulated with dexamethasone as one third of the typical dose, with good treatment results and no discernible side effects.In addition, the mice that received the drugs delivered via nanoparticles survived longer than those that received the drug administered in the traditional way (4).

In another preclinical study Uckun F et al developed nanoparticle (NP) constructs of WHI-P131. WHI-P131 (CAS 202475-60-3) is a dual-function inhibitor of JAK3 tyrosine kinase that demonstrated potent in vivo anti-inflammatory and anti-leukemic activity in several preclinical animal models (5). Notably, WHI-P131-NP was capable of causing apoptotic death in primary leukemia cells from chemotherapy-resistant acute lymphoblastic leukemia (ALL) as well as chronic lymphocytic leukemia (CLL) patients. WHI-P131-NP was also active in the RS4;11 SCID mouse xenograft model of chemotherapy-resistant B-lineage ALL. The life table analysis showed that WHI-P131-NP was more effective than WHI-P131 (P = 0.01), vincristine (P<0.0001), or vehicle (P<0.0001). These experimental results demonstrate that the nanotechnology-enabled delivery of WHI-P131 shows therapeutic potential against leukemias with constitutive activation of the JAK3-STAT3/STAT5 molecular target (5).

Summary:

Acute Lymphoblastic Leukemia (ALL) is a pediatric type of cancer that affects adults to lesser degree. The current rate of cure if 80% in children whereas in adults only 30-40% will survive. Much of the success is due to understanding the mechanisms that lead to the development and progression of cancer. Several gene mutations and gene-translocation have already been identified, and targeting them enabled some of the major success in curing these kids.

Thus far, nanotechnology has been mainly focusing on solid tumors affecting adults. Not much attention is been made on childhood cancer in general and hematopoietic types per se. Two examples of preclinical studies have been discussed above and although they show promise in treatment and reduction of side effects, yet additional research is needed to evaluated their effect in human clinical trials.

Ref:

1. The Genetic Origin of Childhood Acute Lymphoblastic Leukemia (ALL). Reported by Aviva Lev-Ari, PhD, RN. March 20, 2013 http://pharmaceuticalintelligence.com/2013/03/20/the-genetic-origin-of-childhood-acute-lymphoblastic-leukemia-all/

2. Ching-Hon Pui, Leslie L Robison, A Thomas Look. Acute lymphoblastic leukaemia. Lancet 2008; 371: 1030–43.

http://www.med.upenn.edu/timm/documents/PuiLookLancetLeukemiareview.pdf

3. Wendy Stock. Adolescents and Young Adults with Acute Lymphoblastic Leukemia. Hematology December 4, 2010 vol. 2010 no. 1 21-29. http://asheducationbook.hematologylibrary.org/content/2010/1/21.full

4. Vinu Krishnan, Xian Xu,, Sonali P. Barwe, Xiaowei Yang, Kirk Czymmek, Scott A. Waldman, Robert W. Mason, Xinqiao Jia, and Ayyappan K. Rajasekaran. Dexamethasone-Loaded Block Copolymer Nanoparticles Induce Leukemia Cell Death and Enhance Therapeutic Efficacy: A Novel Application in Pediatric Nanomedicine. Mol. Pharmaceutics 2012 ahead of print.

http://pubs.acs.org/doi/abs/10.1021/mp300350e?prevSearch=Rajasekaran&searchHistoryKey=

5. Uckun FM, Dibirdik I, Qazi S, Yiv S. Therapeutic nanoparticle constructs of a JAK3 tyrosine kinase inhibitor against human B-lineage ALL cells. Arzneimittelforschung 2010; 60(4): 210-217.

http://www.ncbi.nlm.nih.gov/pubmed/20486472