Cutting edge research to cancer control

1. GLYCOSAMINOGLYCAN
MALARIA PROTEIN IN
CANCER CONTROL
MMADU AKPEVWE PRINCEWILL &
AMUDA THARHEER
Parasitology unit, Department of Zoology,
University of Ibadan.
by
28/09/2016

2. INTRODUCTION
• Cancer is a genetic disease caused by alteration of
specific genes (Karp, 2010).
• 8.2 million cancer related cases die annually (WHO,
2012).
• 70% of cancer related death are from Africa, Asia,
Central and South America (Karp, 2010).
• Present cancer treatment lacks the specificity needed
to kill cancer cells without harming normal cells.

3. How do normal cells become cancerous?
Selection within tumor for cancerous cells
Figure 1 Source: www.camcer.com

4. • Malignant tumors can invade other tissues and may kill the organism
Tumor
Figure 2
Glandular
tissue
1 2 3A tumor
grows from a
single cancer
cell.
Cancer cells
invade neighboring
tissue.
Lymph
vessels
Cancer cells spread
through lymph and
blood vessels to
other parts of the
body.
Metastasis
Source : www.cancerfacts.com

5. Fig. 3 Source: Miller et al., 2002
BINDING OF INFECTED RBCs TO PLACENTA TROPHOBASTS

6. Fig 3 Adapted from Salanti et al., 2015rVAR2-DT targeting cancer cell

7. VAR2CSA binds to a distinct placental-type Chondroitin
sulfate
• CSA is commonly expressed in the placenta and at lower
levels in the extracellular matrix of other endothelial
tissues.
• The adhesion of infected erythrocytes to placental tissue is
highly specific for CSA and is not inhibited by other
GAGs (Alkhalil et al., 2000).
• I.E isolated from placentas have a unique adhesion
property that is different from parasites collected from
non-pregnant individuals (Smith et al., 2001; Fried and
Duffy, 1996).

8. Fig 4
VAR2CSA binds to a distinct placental-type Chonroitin sulfate
Adapted from Salanti et al., 2015

9. Fig 5
A. VAR2CSA
expressing
erythrocyte binding
to cancer cells in
vitro
B. rVAR binding to
cancer cell lines.
Binding is rVAR
conc. dependent
and is inhibited by
soluble CSA
Expression of placental CS in cancer cells.

10. C D
E
VAR2CSA expressing P.
falciparum infected
erythrocytes adhered to C32
cells and this interaction could
be completely blocked by
purified CSA
Expression of placental CS in cancer cells cont.
Adapted from Salanti et al., 2015Fig 6

11. INTERNALIZATON AND INVIVO LOCALIZATION
OF rVAR2
• pl-CS modification in malignant tumors suggests that VAR2CSA may
be utilized to deliver cytotoxic payloads directly to the tumor
microenvironment.
• Alexa488-labeled rVAR2 (rVAR2-A488) rapidly bound to human
colon cancer cells(Salanti et al., 2015).
• To visualize rVAR2 tumor sequestration, an Alexa750 near-infra red
(NIR) fluorescent probe was conjugated to rVAR2 (rVAR2-NIR).
• The rVAR2-NIR was administrated IV into PC-3 tumor bearing mice
and a NIR signal from the tumor region was observed after 10 min in
vivo and ex vivo.

12. A B
Alexa488-labeled rVAR2
(rVAR2-A488)
rVAR2-A488 rapidly bound
to human colon cancer cells
and was efficiently
internalized within 30 min
C D
Fig 7. Adapted from
Salanti et al., 2015
INTERNALIZATON
AND
LOCALIZATION OF

13. Targeting tumors through the rVAR2 pl-CS Signature
• rVAR2 could be used as a pl-CS specific tumor targeting
system when genetically fused with Diphtheria toxin
(DT388).
• A fusion protein rDT388-VAR2 effectively killed tumor
cell lines of both epithelial and mesenchymal origin with
no effect on normal cells (Salanti et al., 2015).
• Small interfering (si)RNAs targeting the enzymes
responsible for CSA synthesis prevented the cytotoxic
effects of rVAR2-DT in cancer cell lines.

14. • The efficacy of rVAR2-DT was tested in a mouse tumor xenograft
model based on metastatic CRPC cell line (Salanti et al., 2015).
• Results showed that as few as three doses of rVAR2-DT were able
to significantly inhibit growth of PC-3 CRPC tumors in vivo with
no morphologic signs of toxicity (Salanti et al., 2015).
• These data demonstrate that rVAR2 can facilitate efficacious CS
dependent delivery of a cytotoxic compound to CRPC tumors in
vivo with no morphologic evidence of adverse effects on normal
tissues.

15. A
B
C
Adapted from Salanti et al., 2015Fig 8 Targeting tumors through the rVAR2 pl-CS Signature.

16. CONCLUSION
• The placenta and cancer express a similar type of oncofetal
chondroitin sulfate
• Oncofetal chondroitin sulfate is displayed on proteoglycans in cancer
• Recombinant VAR2CSA proteins detect oncofetal chondroitin
modifications
• Human cancer can be broadly targeted by malarial VAR2CSA drug
conjugates in vivo