Cholangiocarcinoma (CCA) is an aggressive type of cancer with limited therapeutic options available. When possible, patients are offered surgical resection, whereas unresectable cases are managed with adjuvant treatment.

Chemotherapy or radiotherapy are usually used to increase the chances of recovery and improve patient’s quality of life and survival. However, despite the recent advances, the survival rate is still a major concern.

“To improve the efficacy of the treatments, recent research is focusing on targeting the DDR [DNA damage response] signaling pathway because cancer cells are able to use DDR to avoid cell death by escaping genotoxic agents induced DNA damage,” said Benchamart Moolmuang and Mathuros Ruchirawat, researchers at the Chulabhorn Research Institute, Thailand.


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Hence, targeting DDR as emerged as a promising strategy for developing cancer-specific therapies. “The idea is that targeting one DDR gene in cancer cells that are defective for other DDR genes might be useful, in order to acquire enough DNA damage to trigger cancer cell death. Thus, targeting DDR genes that are synthetically lethal with a mutation that is common in cancer, can selectively eliminate cancer cells without harming healthy cells,” explained Öykü Gönül Geyik et al. in a recent review article published in Cells.

Several DDR-related genes are altered in CCA. These include IDH1, ARID1A, TP53, CDKN2A, BAP1, FGFR2, PBRM1, KRAS, and PARP, among others. In fact, DDR dysregulation can be so substantial that it is currently recognized as one of the most relevant intracellular pathways in regulating proliferation, apoptosis and, chemoresistance in biliary tract cancers (BTCs), including CCA.

PARP Inhibitors Investigated as Monotherapy in CCA

Different DDR inhibitors (DDRi) have been explored in the context of CCA. Most target members of the poly [ADP-ribose] polymerase (PARP) family. Olaparib (Lynparza®) and niraparib (Zejula) are currently being evaluated as standalone therapies in CCA.

Two active phase 2 trials aim to evaluate olaparib monotherapy. One (NCT03212274) aims to evaluate the efficacy and safety of using olaparib in subjects with CCA, glioma, or other solid malignant tumors with IDH1 or IDH2 mutations. Genetic alterations in IDH1/2 occur in 20% of intrahepatic CCA (iCCA) cases. Evidence suggests that IDH1/2 mutations may improve the sensitivity to PARP inhibitors. The other trial (NCT04042831) aims to evaluate its efficacy in advanced BTC with DDR-related gene mutations.

An open-label, nonrandomized trial (NCT03207347) is investigating the use of niraparib in patients with tumors known to have mutations in BAP1, which encodes for an ubiquitin ligase, and other DDR-related genes. Participants, including patients with refractory CCA and other malignancies, were divided into 2 cohorts according to the presence of known mutation in specific DDR-related genes. The protocol contemplates a once-daily administration of niraparib (300 mg, orally) and aims to assess overall response rate, progression free survival, and overall survival in response to treatment.

PARP Inhibitors in Combination With Other Therapies

Aggressive tumors, including iCCA, may resist to therapeutics with DDRis, reducing their efficacy. “Observing that DDRi alone could be insufficient for clinical use in CCA patients, the combination of DNA-damaging regimens with targeted approaches has started to be considered, as evidenced by many emerging clinical trials,” said Öykü Gönül Geyik et al.

Accordingly, the combination of PARP inhibitors with other DDR targeting compounds and immunotherapy in CCA has received increasing attention over the last years.

Olaparib has been investigated in combination with ceralasertib (NCT03878095), an ataxia telangiectasia and rad3 related (ATR) kinase inhibitor that exhibits potent antineoplastic properties.

Learn about CCA experimental therapies

Additionally, 2 phase 2 trials are studying the combination of olaparib with the monoclonal antibodies durvalamab (Imfinzi®, NCT03991832) and pembrolizumab (Keytruda®, NCT04306367). The combination of ceralasertib with durvalamab is also being evaluated in a open-label, phase 2, umbrella trial (NCT04298021) enrolling advanced BTC patients who have failed to 1st-line chemotherapy.

Durvalumab Plus Chemotherapy Improves Overall Survival in Cholangiocarcinoma

Treatment Combinations With Durvalumab Increase Survival in Patients With CCA

Rucaparib, a PARP inhibitor approved by the US Food and Drug Administration (FDA) for the treatment of ovarian cancer and prostate cancer, is being studied in combination with the monoclonal antibody nivolumab (Opdivo®, NCT03639935) in patients with advanced or metastatic BTC following platinum therapy. Moreover, a single-arm phase 1 study (NCT03337087) aims to determine the tolerability and antidisease effects of a combinatorial regimen that includes rucaparib and chemotherapeutic drugs in patients with gastrointestinal tumors, including CCA.

Additional DDR Targeting Agents Studied in CCA

Compounds targeting the Wee1-like protein kinase (WEE1) showed anticancer activity in several tumors, including CCA, during preclinical tests. Adavosertib and IMP7068, 2 WEE1 inhibitors, progressed into clinical evaluation. Results from phase 1-2 trials indicate an improvement in overall response rate and progression-free survival in patients with different malignancies, including CCA, after treatment with adavosertib. A phase 2 trial is now actively recruiting patients with refractory BRCA1/2-mutated iCCA to further address the efficacy of adavosertib administration.

The inhibition of ataxia-telangiectasia mutated (ATM) and ATR kinases using specific inhibitors was shown to enhance the cytotoxic effects of DNA damaging agents in CCA cells. In addition to ceralasertib, the investigational ATR inhibitor berzosertib showed positive anti-tumor rates in phase 1 studies, as well as good safety and tolerability profiles, alone or in combination with chemotherapeutics, in patients with advanced solid malignancies, including CCA. However, the clinical development and application of ATM and ATR inhibitors is still at early stages.

Additional promising targets include the checkpoint kinases 1 and 2 (CHK1/2) and the serine/threonine kinases DNA-PK and PLK1.

Reference

Gönül Geyik Ö, Anichini G, et al. DNA damage response inhibitors in cholangiocarcinoma: current progress and perspectives. Cells. Published online April 26, 2022. doi:10.3390/cells11091463

Moolmuang B, Ruchirawat M. The antiproliferative effects of ataxia-telangiectasia mutated and ATM- and Rad3-related inhibitions and their enhancements with the cytotoxicity of DNA damaging agents in cholangiocarcinoma cells. J Pharm Pharmacol. Published online January 26, 2021. doi:10.1093/jpp/rgaa050