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SUMMARY:Engineered Therapeutics to Reprogram the Tumour Microenvironment -
  Jai Prakash\, Professor and Chair\, Engineered Therapeutics\, University 
 of Twente
DTSTART:20220621T100000Z
DTEND:20220621T110000Z
UID:TALK175565@talks.cam.ac.uk
CONTACT:Kirsty Shepherd
DESCRIPTION:The cellular and noncellular components of the tumour microenv
 ironment (TME) control cancer cell differentiation\, proliferation\, invas
 ion\, and metastasis. Cells within the TME such as cancer-associated fibro
 blasts (CAFs)\, tumour-associated macrophages (TAMs)\, and other immune ce
 lls secrete factors that interact with cancer cells and stimulate their pr
 oliferation and migration. These factors also negatively affect the therap
 eutic outcome of anti-cancer therapies. Our research goal is to develop en
 gineered therapeutics which can target and reprogram specific cells of the
  TME in order to reverse their pro-tumourigenic and pro-metastatic activit
 y. In the past years\, we have focused on CAFs and TAMs as key target cell
 s within the TME. CAFs are the prominent cell type responsible for inducin
 g desmoplasia (fibrosis) by producing abundant extracellular matrix (ECM) 
 components. Pancreatic cancer is one the deadliest cancer type which is ch
 aracterized with enormous fibrosis. This fibrotic tissue acts as a physica
 l barrier for the penetration of anti-cancer therapies into the tumour. We
  have identified ITGA5\, a fibronectin receptor\, overexpressed on CAFs in
  human pancreatic tumours and contribute to fibrogenesis and ECM remodelin
 g. To block the ITGA5 receptor\, we designed engineered therapeutic peptid
 es which showed reduced activation of CAFs and the ECM production. In vivo
 \, these peptides reduced desmoplasia (collagen deposition) and thereby en
 hanced the efficacy of gemcitabine in different mouse tumour xenograft and
  genetically-engineered KPC mouse tumour model. Recently\, in another stud
 y\, we have developed engineered “tail-flipping” liposomes to target a
 nd re-program TAMs to induce anti-cancer effects. We introduced a phosphol
 ipid (PAPC) into liposomes which could flip the charged hydrophilic tail t
 o the liposome surface and engage with scavenger receptors overexpressed o
 n TAMs. Furthermore\, we delivered a peptidoglycan\, a component of bacter
 ial cell wall\, to TAMs using these liposomes and thereby re-program TAMs 
 into anti-tumoural phenotype in vivo. Altogether\, these studies show that
  re-programming of specific cells within the TME using engineered therapeu
 tics is a vital approach to treat hard-to-treat cancer types.\n\nReference
 s:\n\n1. Heinrich MA\, Mostafa A.M.R.H\, Morton J\, Hawinkels L.W.M.M.\, P
 rakash J. (2021) Mimicking complexity and heterogeneity of pancreatic canc
 er: 3D in vitro to in vivo models. Advanced Drug Delivery Review 174\, 265
 -293.\n\n2. Kuninty PR\, Bansal R\, De Geus G\, Mardhian DF\, Schnittert J
 \, van Baarlen J\, Storm G\, Bijlsma M\, van Laarhoven H\, Metselaar JM\, 
 Kuppen PJK\, Vahrmeijer A\, Ostman A\, Sier CFM\, Prakash J. (2019) ITGA5 
 inhibition in pancreatic stellate cells attenuates desmoplasia and potenti
 ates efficacy of chemotherapy in pancreatic cancer. Science Advances Sep 4
 \;5(9):eaax2770. doi: 10.1126/sciadv.aax2770.\n\n3. Kuninty PR\, Binnemars
 -Postma KA\, Jarray A\, Heinrich MA\, Pednekar K\, ten Hoopen H\, Storm G\
 , van Hoogevest P\, den Otter WK\, Prakash J. (2022) Cancer immune therapy
  using engineered ‛tail-flipping’ nanoliposomes targeting alternativel
 y activated macrophages. Nature Communications (in press)
LOCATION:Join Zoom Meeting  https://eng-cam.zoom.us/j/85374365238?pwd=djVC
 cTdhaFYrQkgycVVYU0RTZXdnZz09  Meeting ID: 853 7436 5238 Passcode: 697954
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