News Release

Title
Identification of a novel potent therapeutic strategy that the targeting of long non-coding RNA for thetreatment of lethal pancreatic ductal adenocarcinoma.
Key Points

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human malignancies. The
poor prognosis is due to the lack of potent chemotherapy against PDAC.

Many of the patients with PDAC suffer from resistance and toxicity to chemotherapy. Therefore,
development of a cancer-specific therapeutic strategy to strengthen the effect of chemotherapy andovercome the resistance to chemotherapy is imperative.

We demonstrated long non-coding RNA TUG1 to be frequently upregulated in PDACs, causing
acquisition of 5-FU resistance via enhancement of 5-FU catabolism.

We made a new therapeutic drug that the targeting of TUG1 by anti-TUG1 coupled with our newcancer-specific drug delivery system (TUG1-DDS). Intravenous treatment with 5-FU plus TUG1DDS efficiently repressed PDAC growth in PDAC xenograft mouse model.

Our data provided a strong and novel rationale for targeting TUG1 as a practical therapeuticapproach to treat PDACs.

Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human malignancies, inwhich overall median survival is less than five months and the five-year survival rate is around 10%.
The poor prognosis is due to lack of potent therapeutic strategies against PDAC. Particularly, incase of treatment failure, many of the patients with PDAC inevitably suffer from resistance tochemotherapy. Overcoming drug resistance is one of the biggest challenges in cancer

chemotherapy. In this study, we examine whether targeting the long non-coding RNA TUG1 could
be an effective therapeutic approach to overcome drug resistance in PDAC. We demonstrated
TUG1 to be frequently upregulated in PDACs, causing acquisition of 5-FU resistance via
enhancement of 5-FU catabolism. We made a new therapeutic drug that the targeting of TUG1 byanti-TUG1 coupled with our new cancer-specific drug delivery system (TUG1-DDS). Intravenoustreatment with TUG1-DDS and 5-FU significantly suppressed PDAC tumor growth compared to5-FU treatment alone. This novel approach using TUG1-DDS in combination with 5-FU may serveas an effective therapeutic option to attenuate DPD activity and meet appropriate 5-FU dosage
requirements in targeted PDAC cells, which can reduce the systemic adverse effects ofchemotherapy.

Research BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human malignancies.
Although surgical resection is the only curative therapy for PDAC, only 20% of patients are
considered to be a candidate for surgical resection. Almost of patients with PDAC have undergone
5-FU or Gemcitabine based chemotherapy. The overall survival of patients receiving thatchemotherapy is still less than a year. Furthermore, many of the patients with PDAC suffer fromresistance and toxicity to chemotherapy. In this study, we aim to elucidate the mechanism of
resistance to chemotherapy and to identify a cancer-specific therapeutic strategy to strengthen theeffect of chemotherapy.
Research Results
TUG1 was expressed at significantly
higherlevels

acrossPDAC

tissuescompared to normal pancreatic tissues.
Mechanistically,

TUG1

antagonizedmiR-376b-3p and upregulated DPD. Onlya small fraction of 5-FU is converted intocytotoxic metabolites intracellularly, while
80% of 5-FU is catabolized to thenon-cytotoxic

metabolites

bytheenzymatic activity of DPD. There is aconsistentrelationshipbetweenthe

enzymaticactivity

DPDandof5-FU.

pharmacologicalofactivity

Therefore, aberrant upregulation of DPD
might

be

the

keydeterminants

ofresistance to 5-FU in PDACs. Our results
showed that TUG1 depletion induced

susceptibility to 5-FU together with a decreased DPD expression in 5-FU resistant pancreatic cell,
whereas overexpression of TUG1 acquired resistance to 5-FU together with an increased DPD
expression in 5-FU sensitive cell (Figure 1). We demonstrated TUG1-miR376b-3p-DPD axis to be
frequently dysregulated in PDACs, causing acquisition of 5-FU resistance via enhancement of 5-FU
catabolism. Next, we made a new therapeutic drug that the targeting of TUG1 by anti-TUG1
coupled with cancer-specific drug delivery system (TUG1-DDS). We found TUG1-DDS toaccumulate in tumor cells (Figure 2). Finally, we examined the effect of combination therapy with5-FU and TUG1-DDS in PDAC xenograft mouse model. Remarkably, combination therapy using
5-FU and TUG1-DDS further suppressed the tumor growth than 5-FU alone (Figure 3).

Research Summary and Future Perspective
In the current study, we demonstrated TUG1-miR376b-3p-DPD axis to be frequently dysregulated
in PDACs, causing acquisition of 5-FU resistance via enhancement of 5-FU catabolism. Treatment
with TUG1-DDS, which can reduce or avoid the systemic adverse effects, combined with5-FU-based chemotherapy, might be a promising therapeutic approach against PDACs, particularly
those with resistance to 5-FU.
We aim to perform clinical trial of a TUG1-DDS for patients with PDAC in order to demonstratethat inhibition of TUG1 is a practical therapeutic approach for PDAC with patients (Figure 4).

Publication
Journal: Cancer Res, 1st March, 2021
Title: Cancer-specific targeting of taurine upregulated gene 1 enhances the effects of chemotherapy inpancreatic cancer

Author:Yoshihiko Tasaki, Miho Suzuki, Keisuke Katsushima, Keiko Shinjo, Kenta Iijima, Yoshiteru
Murofushi, Aya Naiki-Ito, Kazuki Hayashi, Chenjie Qiu, Akiko Takahashi, Yoko Tanaka, Tokuichi
Kawaguchi, Minoru Sugawara, Tomoya Kataoka, Mitsuru Naito, Kanjiro Miyata, Kazunori Kataoka,Tetsuo Noda, Wentao Gao, Hiromi Kataoka, Satoru Takahashi, Kazunori Kimura and Yutaka Kondo.
Affiliation:
1. Division of Cancer Biology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho,Showa-ku, Nagoya, Aichi, 466-8550, Japan.
2. Department of Clinical Pharmaceutics, Nagoya City University Graduate School of MedicalSciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan.
3. Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate
School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601,
Japan.
4. Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of
Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan.
5. Pancreas Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029,
People’s Republic of China.
6. Project for Cellular Senescence, Cancer Institute, Japanese Foundation for Cancer Research,
3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
7. PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama,332-0012, Japan.
8. Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake,
Koto-ku, Tokyo, 135-8550, Japan.
9. Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The
University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
10. Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
11. Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14
Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan.
12. Institute for Future Initiatives, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033,
Japan.
13. Director's Room, Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake,
Koto-ku, Tokyo, 135-8550, Japan.
DOI: 10.1158/0008-5472.CAN-20-3021