Transcript TOXINS CytotoxicProstateCancerTreatment PPTx

Prostate Cancer and Cytotoxic Treatment
Found in the Sea Anemone, Stichodactyla
helianthus
By: Diem Nguyen, Rachel Jones and David Waid
University of New Mexico
Department of Biology
Spring 2012
Introduction
 History of Prostate Cancer:
 Leading cause of illness and death among men in the
United States and Western Europe
 2011: An estimated 240,900 men were diagnosed with
prostate cancer
 33,720 deaths
Underlying causes of disease
 ~ 42% caused by genetic influences
 Mutations
 Genetic instability
 Heritable traits, etc.
 ~ 58% caused by environmental factors
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Diet
Lifestyle
Carcinogens
Inflammation, etc.
Conventional Treatments
 Traditional Chemotherapy
 Radical prostatectomy
 Direct implantation of radioactive seeds into the prostate
 Castration via surgical and hormonal methods
Prospective Clinical Trials
 Immunotoxin Chemotherapy on cancer cells
 Shown to be effective in eliminating tumor growth
 Mice, adult Hodgkin's and non-Hodgkin's lymphoma, pediatric lymphocytic
leukemia
 Fact: Traditional Immunotoxins require internalization and
translocation into the cell in order to enact a cytotoxic effect
 Problem: This could induce other cellular responses
 Excessive destruction of healthy cells
 Degradation of lysosomes
 Solution: “Stay tuned…”
What are Immunotoxins (ITs)?
 Synthesized, chimeric molecules
 Cytotoxic agent + monoclonal antibody
 Targets tumorous lesions
 Cytotoxic and lytic effects on cancer cells
 Primary Candidate:
 Sticholysin I (StI)
 a cytolysin found in the sea anemone, Stichodactyla helianthus
 may be a beneficial immunotoxin for the cytolytic destruction of
prostate tumor cells
Sticholysin I (StI)
 A pore-forming toxin (actinoporin)
 Induce cellular lysis via contact with plasma membrane, causing lethal
pore development
 Able to irreversibly bind and interact with cell membranes
 Tryptophan rich region at N-terminus of toxin acts as the binding site to
anchor itself to the plasma membrane, promoting pore-formation
Proposal for Cytotoxic Chemotherapy
Treatment
 Recall…
 Fact: Traditional Immunotoxins require internalization and translocation into the
cell in order to enact a cytotoxic effect
 Problem: This could induce other cellular responses
 Excessive destruction of healthy cells
 Degradation of lysosomes
 Proposed Solution:
 Provide a modified cytolysin, Sticholysin I (StI), enabling it to
bind more selectively to tumor cells, inducing cytotoxic activity
on prostate cancer cells.
Mechanism of Action
Step 1: Block tryptophan binding site of N-terminus by introduction of
cysteine residues providing a peptide link between StI and a avidin
molecule.
Cysteine residues
Avidin
molecule
StI
The avidin, and cysteine residue complex will render tryptophan binding site
inactive. New cytotoxin complex will bind to the cell membranes of prostate
cells
Mechanism of Action (Cont.)
Step 2: Insertion of newly synthesized cytotoxic agents into tumor via
trans-rectal ultrasound (TRUS).
 a prostate tumor-secreted protease (i.e. matrix metalloproteinases) will
cleave Cys-Cys peptide bond
 Avidin complex will release from StI, revealing tryptophan binding
region
 Cleaving of cysteine complex from StI will reactivate the pore-forming
cytotoxin
 Exposure of binding region will allow it to anchor itself on the plasma
membrane and bore holes in cancerous cells
 This will induce pore-forming activity of tryptophan on tumor cells
within the vicinity of the agent
 Colloidal osmotic shock will ensue, resulting in the apoptosis of the
cells
Results
 Studies have demonstrated that advanced prostate
cancer frequently involves bone metastases.
 Our research has shown that pore-forming cytotoxins
may be effective in inhibiting tumor proliferation,
thereby, serving as an viable anti-cancer treatment,
while concurrently providing anti-metastasis tactics.
 Additionally, side effects and excessive destruction of
healthy cells are minimized as the treatment is only
effective within a certain radius of action.
Implications of Treatment
 Predict that greatest therapeutic benefit of treatment will be in individuals
with early onset prostate cancer
 This may be attributed to a more rapid upregulation of cellular processes
upon exposure to cytotoxin
 Effective filter mechanisms with selected phenotypes either decreases
later in life or cancer processes adapt to circumvent defenses
 Due to cancerous cells rapidly proliferating and disseminating, they may
eventually acclimate to immunotoxic treatments
Limitations of Research
 Lack of specificity of avidin ligand may cause lysis of normal cells
prior to reaching target tumor
 Possible solution: Attach an antibody to the avidin end of ligand to
further increase specificity
 Cytolysin has dependence on sphingomyelin levels in order to
initiate interaction with cellular membranes.
Discussion
Reducing Side Effects
 Pore-forming cytotoxins are highly potent and lyse most
cells
 Further trials should be conducted to determine safe
amounts for administration
 Careful titration of immunotoxin must be observed by
MRI and other imaging technology
Discussion Cont.
 Influences on to consider for Prostate Cancer:
 Diet
 High levels protein has been shown to be a potent
carcinogenic factor
 Carcinogens; air pollutants, environmental chemicals
 Lifestyle choices (i.e. smoking, inactivity)
 Genetic predispositions
Future Research
 Produce an immunotoxin with specificity that targets
only cancerous cells via attachment of antibody to
avidin end of ligand
 Allow for recognition of tumor cell surface antigen
 Provide immunotoxin treatment to individuals with a
restricted protein intake
 Examine efficacy of diet and therapy versus therapy
alone
 We hypothesize that a greater therapeutic benefit would be
observed in patients with low protein consumption and
concurrent treatment
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