2020 Joint Usage and Research Report
Title of Research Project

Targeting PARP7 and Mono-ADP-ribosylation to Improve Cancer
Immunotherapy

Institution
Applicant

University of OsloJob title

Professorand Name

Jason Matthews

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Under35

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Institution
Research

Job titlecollaborators

and Name(Please add lines as

Institution

appropriate)

Job title
and Name

Host researcher at IGM
PurposeoftheResearch

Professor Akinori Takaoka
Pancreatic cancer (PC) is a devastating disease with a very poor

Project

prognosis. The composition and immune status of the tumour(approx. 250 words)

microenvironment (TME) is central for disease progression. Cancer
immunotherapy is a rapidly growing field and represents a paradigm
shift in cancer treatment offering a new therapeutic approach tosurgery, conventional chemotherapy, and radiation therapy. One of
the most studied targets is the inhibition of programmed deathligand 1 (PDL1) and its receptor PD1, which when engaged prevents
the overstimulation of the immune system by deactivating T cells.
Type I interferons are central regulators of tumour immune cell
infiltration and activation. Together with the Takaoka lab, werecently reported that Poly-ADP-ribose polymerase 7(PARP7/TIPARP), a negative regulator of type I signalling. The
actions of PARP7 on tumour cells allow them to “hide” from theimmune system by inhibiting IFN production. Thus, restoring
interferon signalling, would in essence release the “brake” thatcancer uses to evade the immune system.
The purpose of this application is to determine if the loss orinhibition of PARP7 alone or in combination with immune checkpoint
inhibition boosts the anti-tumour effects in intro and in vivo modelsof PC.
We have three research objectives: (1) Determine how genetic andpharmacologic targeting of PARP7 signalling influences PC growth;(2) Investigate the role of PARP7 in T cell mediated cancer killing (3)Characterize how PARP7 signalling influences PC growth insyngeneic mouse studies. Our proposal will determine the role ofPARP7 as a potential therapeutic target on its own or used as
combination treatment with cancer immunotherapy for PC.

Development of the Research

Unfortunately, like many other things during the past year, theProject and Resultscoronavirus pandemic has reduced out research output. Because(approx.. 850 words)of the general travel ban in Norway and Japan, physical meetings*Enter the number of web

from April 1st 2020 until March 31st 2021 were not possible. Wemeetings.

did, however, exchange research productivity updates via email. A
formal web-based meeting was not organized, but will be done in
the future until other alternatives are possible.
Over the past year, my lab has established the IFN type signaling
analysis protocol with the help of Prof Takaoka’s lab and theirwillingness to shar their expertise and protocols with us. We haveused the platform to characterize a number of geneticallymodified pancreatic cancer cell lines in which we have knockout
PARP7 expression using CRISPR-Cas. We have created PARP7knockouts in human AsPC1 and Capan-1 cells and in mouse
K8484 and CR704 cells. The Two mouse cell lines were generated
from

spontaneous

pancreatictumours

LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre(KPC)

frommouseline. As expected PARP7 knockout enhances Type I IFN signaling.
We are characterizing their growth conditions and viability. We
are now using various approaches (RNA-seq) to identify specificgene signatures that are changed by the loss of PARP7. Theseexperiments are proposed under research objective 1 of ourresearch plan. We have also generated and fully characterized
and highly specific anti-PARP7 antibody that will be crucial to
fully characterize PARP7’s role in pancreatic cancer. The antibody
works best at detecting mouse PARP7, but plans are underway todevelop one that detects human PARP7 as well. The antibody is amouse monoclonal which give us an unlimited supply by purifying
it from the hybridomas.
We have tested selective and specific PARP7 inhibitors in the invitro models. We have purchased a commercially available PARP7inhibitor

thatwas(https://ribontx.com),

identified
known

as,byRibon

RBN-2397.

Therapeutics
RNB-2397iscurrently in a Phase 1 clinical trial designed to assess its

anti-tumor activity in patients with advanced-stage solid tumors(NCT04053673). Ribon presented the anti-tumor effects ofRBN-2397 at an AACR webinar in May 2020. They reported
dose-dependent reduction of non-small-cell lung carcinoma(NCI-H1373) tumor growth at 30 mg/kg in a xenograft model.
RBN-2397-mediated PARP7 inhibition prevented CT26 colon
tumor growth in a syngeneic mouse model, which was dependenton type I IFN signaling. These are very exciting studies that will
try to confirm in our PARP7 cell and mouse models. As expected,
in our hands the pharmacological inhibition phenocopies what we
observe in the PARP7 knockout cells. We have just recently
started the preliminary studies on the co-culture experiments toinvestigate the role of the PARP7 in T cell mediated. Thosestudies are ongoing and will be one of our focus this year. Finally,
we are poised to start the syngeneic cancer cell experiments using
our Parp7 mutant mice and the various genetically modified
Parp7 knockout mouse pancreatic cancer lines that we havegenerated.
The project continues to develop and we expect generateinteresting and significant data during the coming year.
The work is in progress and was not presented at a meeting orPublication*Entertheconferenceorinformationofjournal(vol.

conference in 2020

page. Year.) where the above
work was presented.

No publications this past year.