The evolution into personalized therapies in pancreatic ductal adenocarcinoma: challenges and opportunities

Tesfaye, Anteneh; Kamgar, Mandana; Azmi, Asfar S.; Philip, Philip A.

doi:10.1080/14737140.2018.1417844

Cited by 36 publications

(35 citation statements)

References 201 publications

(219 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Regarding the correlation between immunologic function and oncologic outcome, increasing numbers of tumour antigen‐specific CD8+ T lymphocytes and natural killer cells are associated with better prognosis in PDAC . On the basis of these studies, attempts have been made to apply immunological methods to patient treatment . However, it is not easy to apply the molecular‐level mechanisms underlying these microenvironments directly to clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Association of preoperative total lymphocyte count with prognosis in resected left‐sided pancreatic cancer

Rho

Hwang

Chong

et al. 2019

ANZ Journal of Surgery

View full text Add to dashboard Cite

Background: Immunologic factors such as neutrophil-lymphocyte ratio and platelet-lymphocyte ratio play an important role in predicting the oncologic outcome of patients in pancreatic ductal adenocarcinoma (PDAC). It is hypothesized that host immunity represented by total lymphocyte count at diagnostic stage would influence oncologic outcome in left-sided PDAC. Methods: Between January 1992 and August 2017, total of 112 patients who underwent distal pancreatectomy for left-sided PDAC were included and analysed. Results: At the time of the diagnosis, total lymphocyte count at diagnosis of left-sided PDAC was 1.8 AE 0.7 10 3 /μL (mean value AE standard deviation). Among different cut-off values, 1.7 showed most powerful significant differences in long-term oncologic outcomes. The patients with preoperative lymphocyte count (≤1.7) was associated with early recurrence (median 8.4 months versus 18.1 months, P = 0.011) and shorter survival (median 18.6 months versus 35.9 months, P = 0.028). Patients with preoperative total lymphocyte count over 1.7 showed higher white blood cell count (P < 0.001), platelet count (P = 0.039), neutrophil count (P = 0.004) and monocyte count (P = 0.001). However, more interestingly, neutrophil-lymphocyte ratio (P < 0.001) and platelet-lymphocyte ratio (P < 0.001) were found to be significantly higher in those with total lymphocyte count less than 1.7. Lymphocyte to monocyte ratio was inversely related to preoperative total lymphocyte count (P < 0.001). Only age was identified to be significantly different (P = 0.007). However, other clinicopathological parameters generally known to be related to tumour aggressiveness, were not different between two groups. Conclusion: In conclusion, preoperative total lymphocyte at diagnostic stage is simple, and good prognostic factor in left-sided pancreatic cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

Association of preoperative total lymphocyte count with prognosis in resected left‐sided pancreatic cancer

Rho

Hwang

Chong

et al. 2019

ANZ Journal of Surgery

View full text Add to dashboard Cite

show abstract

“…The EGFR family (EGFR also known as HER) is a subset of receptor tyrosine kinases that activate and regulate diverse processes, including cell survival, proliferation, differentiation, and migration . It has been shown to be activated in many epithelial cancers such as colorectal, breast, and lung cancers .…”

Section: Discussionmentioning

confidence: 99%

Internal enhancement of DNA damage by a novel bispecific antibody‐drug conjugate‐like therapeutics via blockage of mTOR and PD‐L1 signal pathways in pancreatic cancer

et al. 2019

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) is a refractory malignant tumor with poor prognosis, limited chemotherapeutic efficacy, and only about 5% of 5‐year survival rate. We generated a dual‐targeting ligand‐based lidamycin (DTLL) to investigate its efficacy against pancreatic cancer after preparing its precursor, DTLP. DTLP was shown specifically binding to EGFR and HER2 on cell surface, followed by endocytosis into cytoplasm of pancreatic cancer cells. DTLL significantly promoted apoptosis and cell cycle arrest at G2/M stages and inhibited cell proliferation. Pancreatic tumors of either MIA‐paca‐2 cell line‐derived (CDX) or patient‐derived xenograft (PDX) mouse models were significantly regressed in response to DTLL. It suggested that DTLL might be a highly potent bispecific antibody‐drug conjugate (ADC)‐like agent for pancreatic cancer therapy. LDM is known to function as an antitumor cytotoxic agent by its induction of DNA damage in cancer cells, therefore, DTLL, as its derivative, also showed similar cytotoxicity. However, we found that DTLL might reverse the AKT/mTOR feedback activation induced by LDM at the first time. The results from both in vitro and in vivo experiments suggested that DTLL enhanced DNA damage via EGFR/HER2‐dependent blockage of PI3K/AKT/mTOR and PD‐L1 signaling pathways in cancer cells, leading to the inhibition of cell proliferation and immunosurveillance escape from pancreatic tumor. Our studies on DTLL functional characterization revealed its novel mechanisms on internal enhancement of DNA damage and implied that DTLL might provide a promising targeted therapeutic strategy for pancreatic cancer.

show abstract

“…2,3 A number of new agents are in active investigation, and the tumor stroma has emerged as a key focus of research in pancreatic cancer. [4][5][6][7] Primary and metastatic lesions are characterized by a dense desmoplastic stroma in which cancer cells are sparsely scattered. 8 Hyaluronic acid (hyaluronan, or HA) is a major component of this extracellular matrix.…”

Section: Introductionmentioning

confidence: 99%

Phase IB/II Randomized Study of FOLFIRINOX Plus Pegylated Recombinant Human Hyaluronidase Versus FOLFIRINOX Alone in Patients With Metastatic Pancreatic Adenocarcinoma: SWOG S1313

Ramanathan

McDonough

Philip

et al. 2019

JCO

Self Cite

254

162

View full text Add to dashboard Cite

PURPOSE Pegylated recombinant human hyaluronidase (PEGPH20) degrades hyaluronan (HA) and, in combination with chemotherapy, prolongs survival in preclinical models. The activity of PEGPH20 with modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) was evaluated in patients with metastatic pancreatic cancer (mPC). MATERIALS AND METHODS Patients had untreated mPC, a performance status of 0 to 1, and adequate organ function. Tumor HA status was not required for eligibility. After a phase Ib dose-finding study of mFOLFIRINOX plus PEGPH20, the phase II open-label study randomly assigned patients (1:1) to the combination arm or to mFOLFIRINOX alone (n = 138). The primary end point was overall survival (OS). RESULTS PEGPH20 dosages of 3 µg/kg every 2 weeks were more tolerable than twice-weekly dosages used in the phase I study, so 3 µg/kg every 2 weeks was the phase II dosage. An amendment instituted enoxaparin prophylaxis in the PEGPH20 combination arm as a result of increased thromboembolic (TE) events. The planned interim futility analysis when 35 deaths (of 103 analyzable patients) occurred resulted in an OS hazard ratio (HR) of 2.07 that favored the control arm, and the study was closed to accrual. The treatment-related grade 3 to 4 toxicity was significantly increased in the PEGPH20 combination arm relative to control (odds ratio, 2.7; 95% CI, 1.1 to 7.1). The median OS in the mFOLFIRINOX arm was 14.4 months (95% CI, 10.1 to 15.7 months) versus 7.7 months (95% CI, 4.6 to 9.3 months) in the PEGPH20 combination arm. CONCLUSION Addition of PEGPH20 to mFOLFIRINOX seems to be detrimental in patients unselected for tumor HA status. This combination caused increased toxicity (mostly GI and TE events) and resulted in decreased treatment duration compared with mFOLFIRINOX alone. The median OS in the mFOLFIRINOX control arm (14.4 months) is, to our knowledge, the longest yet reported and can be considered for patients with good PS.

show abstract

The evolution into personalized therapies in pancreatic ductal adenocarcinoma: challenges and opportunities

Cited by 36 publications

References 201 publications

Association of preoperative total lymphocyte count with prognosis in resected left‐sided pancreatic cancer

Association of preoperative total lymphocyte count with prognosis in resected left‐sided pancreatic cancer

Internal enhancement of DNA damage by a novel bispecific antibody‐drug conjugate‐like therapeutics via blockage of mTOR and PD‐L1 signal pathways in pancreatic cancer

Phase IB/II Randomized Study of FOLFIRINOX Plus Pegylated Recombinant Human Hyaluronidase Versus FOLFIRINOX Alone in Patients With Metastatic Pancreatic Adenocarcinoma: SWOG S1313

Contact Info

Product

Resources

About