1. Opportunities for Addressing Unmet Clinical Need in Brain Cancer
Colin Watts

2. Brain Cancer has a disproportionate burden of disease on the individual that is poorly recognised
Brain Cancer accounts for 2% of cancers but 7% of cancer deaths
Astrocytic tumours are the third leading cause of cancer related death in middle aged men
Astrocytic tumours are the fourth leading cause of death among women aged 15-34

3. Glioblastoma is biologically complex at presentation

4. So how can we develop multimodal precision therapeutics?

5. We can interrogate spatial and temporal intratumour heterogeneity in patients in real time to establish a biological rationale for drug targeting
Figure 5. Reconstruction of GB progression. The combination of sampling information, copy number and gene expression profiles, and molecular clock data enable the reconstruction of tumor progression, as shown here for SP42. The evolution of the malignancy is illustrated by the accumulation of CNAs in different parts of the tumor and the corresponding variation in the gene expression profile, which reveals that T4 is classified as a different subtype (mesenchymal) with respect to the rest of the neoplasm (proneural). Moreover, we report the presence of variable numbers of sub-clones in each tumor fragment.

6. We can develop a patient-derived xenogeneic platform for high-throughput screening & technology development

7. An example of multimodal therapeutics through nanotechnology
Setua et al 2014 Nanoscale 6 (18)

8. Aim of the project
Development of peptide functionalized drug-gold nanoparticle conjugate for targeted chemoradiotherapy of GBM
(We use patient derived GBM cells)
As an alternative we proposed to develop peptide functionalized drug-gold nanoparticle conjuagte for cancer cell targeted chemoradiotherapy of GBM.
Schematic showing how the proposed nanosystem will work : the nanomedicine will be made of gold nanoparticle surface functionalized with anti-cancer drug cisplatin. MUA (mercaptoundecanoic acid ) works as a linker between drug and the gold nanoparticle. After entering in the cancer cell by endocytosis, cisplatin will be released from the gold nanoparticle due to the acidic pH of the late endosome. Free ciplatin will bind with the guanine of the DNA resulting in intrastrand and interstarnd DNA cross-link. This cross links will initiate DNA damage. In presence of radiation, gold nanoparticles and platinum of the drug will emit ionizing photoelectron and Auger electrons (because of photoelectric effect, high atomic number of gold and platinum help in this process). These electrons will ionize the water inside cells and will produce large amount of reactive oxygen species (ROS). ROS will further damage the DNA and cellular proteins. These will kill the cancer cell.
(MUA)
AuNP: Gold nanoparticle

9. Radiosensitizing potential of AuNP
Control + RT
AuNP-HSA + RT
AuNP-PEI + RT
Growth Curve : GBM cell line
GBM xenograft model
P =
Control
Next we checked the radiosensitizing capacity of the conjugate by DNA damage (yH2AX) assay, Apoptosis (Caspase-3) assay and growth curve. (representative image and quantification of the signals)
We found increased DNA damage and higher caspase 3 activation in case of AuNP-PEI. This initiated higher cell death in growth curve. However, the cells could recover from the damage.
In vivo result also shows that the survival of the AuNP-PEI group is not significantly higher than the control.
So, gold nanoparticle mediated radiosensitization is not a effective therapy for these patient derived GBM cells.
Control + RT
AuNP-PEI
AuNP-PEI + RT
* = P < 0.05, ** = P < 0.01, *** = P < 0.001
AuNP + RT can not decrease the growth of GBM cells effectively.

10. Radiosensitizing potential of AuNP-Pt
Control+RT
AuNP-MUA+ RT
AuNP-Pt + RT
* = P < 0.05
*** = P < 0.001
In presence of radiation excellent synergy of cisplatin mediated chemotherapy and gold + platinum (of cisplatin) mediated radiosensitization was found
AuNP-Pt + RT can decrease the growth of GBM cells significantly.

11. What do we need? Targeted delivery specifically to tumour cells
Capacity to deliver multiple drug payloads
Maximise therapeutic efficacy
Minimise toxicity associated with combinatorial therapeutics
Local and systemic therapies
Real-time diagnostics that can control for biological heterogeneity

12. How can we do this? cw209@cam.ac.uk
Strategies for tumour-cell targeting
Linking biology & technology
Developing a (nano)technology platform
High-throughput evaluation using validated biological platforms
In silico modelling
Tunable adaptive technology to deliver precison therapeutics