**6. Conclusions**

**5.2. Targeted therapy**

42 Advances in Pancreatic Cancer

(NCT02993731) [85].

A comprehensive genetic analysis of PC showed that these tumors contain an average of 63 genetic alterations in 12 cellular signaling pathways, including Notch pathway [82]. A Phase Ib trial for PC using a combination of Demcizumab (OMP-21M18), a monoclonal antibody against Notch ligand, DLL4, with Gemcitabine and Abraxane, showed some clinical benefits [60]. An antibody against Notch2 and Notch3, Tarextumab, was tested in Phase 2 clinical trials in combination with Gemcitabine and nab-Paclitaxel in patients with metastatic PC. For these patients, the median progression-free and overall survival were 5.6 and 11.6 months, respectively. Gamma secretase inhibitors (GSIs) have been used in clinical trials in PC. For example, a GSI called RO4929097 was safely tolerated in combination with Gemcitabine and achieved clinical antitumor activity and more than 4 months of stable disease. However, the use of GSI has limitations and still represents a challenge because of the increased drug toxicity and lack

Desmoplasia is a target in PC treatment. Hyaluronan, a component of the ECM of PC, is a naturally occurring nonsulfated glycosaminoglycan that was targeted using pegylated hyaluronidase (PEGPH20). In a Phase II study combining Gemcitabine, nab-Paclitaxel, and PEGPH20, there was no difference seen in the survival of PC patients that had this addition to their treatment. Also, due to the ubiquitous nature of hyaluronan, there were unexpected side effects, such as thrombosis. For the Gemcitabine, nab-Paclitaxel, and PEGPH20 study, a subset analysis was performed on the high-hyaluronan patients. In the arm receiving PEGPH20, the response rate was 45% when compared with 31% in controls, which was encouraging, and led to a Phase III clinical trial (HALO301) for patients that had high hyaluronan. In these

STAT3 inhibition has been shown to decreased PC growth in mouse models. Napabucasin decreased STAT3 transcription and tumorsphere formation and showed some efficacy in PC. Napabucasin induced a median progression-free survival of >7.1 months and a median overall survival of >10.4 months in PC patients. Based on these encouraging results, it is now being evaluated in a PC Phase III study in combination with Gemcitabine and nab-Paclitaxel

The expression of leptin in gastroesophageal adenocarcinomas was associated with chemoresistance. Therefore, the addition of leptin antagonists to current chemotherapeutic treatment could represent a new strategy to overcome drug resistance and to improve survival of PC patients. SHLA, a leptin antagonist, increased the sensitivity of resistant gastric cancer cell

LPrA2 was designed and tested in vitro and in vivo in PC xenograft mouse models in our laboratory. LPrA2 is composed by a leptin sequence corresponding to its binding Site III of the leptin molecule. LPrA2 was conjugated to iron-oxide nanoparticles (IONP-LPrA2) to increase its bioavailability and effectiveness to block leptin signaling in cancer cells [28]. IONP-LPrA2 showed no toxicity and did not affect energy balance (body weight or food intake) or general health when it was administered to mice. IONP-LPrA2 reduced the expression of Ob-R, Notch, and PCSC markers. Furthermore, specific inhibition of leptin signaling by IONP-LPrA2 delayed tumor onset and decreased tumor growth in a PC xenograft mouse model. Our data also showed that IONP-LPrA2 could be used as an adjuvant therapy to 5-FU. In PC cells treated

line, AGS Cis5, and the esophageal adenocarcinoma, OE33, to cisplatin [86].

of high specificity to Notch besides other substrates of γ-secretase [83].

studies, Lovenox was included for anticoagulation [84].

PC is a lethal systemic disease that is difficult to detect and treat. This is mainly due to the fact that even patients diagnosed with early stages eventually develop metastasis. The deep abdominal position of the pancreas is an additional factor that delays the onset of specific PC symptoms. Early PC diagnosis and potential cure remain important challenges due to the lack in screening methods and specific biomarkers. PC risk factors, such as high-fat diet, obesity, tobacco, and alcohol consumption, can be modified, leading to prevention of disease occurrence and increased survival. PC desmoplastic stroma, which decreases chemotherapeutic drug delivery to the tumor, is an another current challenge to improve PC survival. Currently, combined chemotherapy strategies are used in selected patients with PC metastatic disease. The identification of novel PC targets is the key for the development of new individualized strategy for prevention and treatment. An emerging and promising area is the relationship between obesity and leptininduced prooncogenic effects in PC, which could also affect chemoresistance and metastasis. In this respect, the use of leptin signaling antagonists as a novel sensitization adjuvant for current chemotherapeutic drugs appears as a potential new strategy to improve treatment effectiveness and patients' survival. The use of leptin signaling antagonists could also make possible the reduction of drug dosage and the improvement of patient quality of life.

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