Alessandra Mosca

Targeting PI3K/Akt/mTOR signaling in cancer

The phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathways are two pathways crucial to many aspects of cell growth and survival, in physiological as well as in pathological conditions (e.g., cancer). Indeed, they are so interconnected that, in a certain sense, they could be regarded as a single, unique pathway. In this paper, after a general overview of the biological significance and the main components of these pathways, we address the present status of the development of specific PI3K, Akt, and mTOR inhibitors, from already registered medicines to novel compounds that are just leaving the laboratory bench.

Clinical outcomes in patients receiving three lines of targeted therapy for metastatic renal cell carcinoma: Results from a large patient cohort

AIM A number of targeted therapies (TTs) are effective in metastatic renal cell carcinoma (mRCC) but clinical outcomes with the sequential use of three TTs have been poorly investigated, this study evaluates their outcome. METHODS Patients with clear cells mRCC treated with three TTs were retrospectively studied. Therapies were classified as vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) or mammalian target of rapamycin inhibitors (mTORi). Progression free survival (PFS), overall survival (OS) and total PFS (tPFS)--defined as the time from start of first-line to progression on third-line treatment--were estimated using the Kaplan-Meier method and curves were compared with log-rank test. RESULTS A total of 2065 patients with mRCC were consecutively treated with first-line TT in 23 centres in Italy. Overall 281/2065 patients (13%) were treated with three TTs. Median OS and tPFS were 44.7 and 34.1 months, respectively and were longer in patients receiving the sequence vascular endothelial growth factor inhibitors (VEGFi)-VEGFi-mTORi compared with those receiving VEGFi-mTORi-VEGFi with a statistical difference in OS (50.7 versus 37.8 months, p = 0.004; 36.5 versus 29.3 months, p = 0.059, respectively). CONCLUSIONS Few patients received three lines of TTs. The sequence VEGFi-VEGFi-mTORi was associated with improved survival with respect to VEGFi-mTORi-VEGFi and primary resistance to first-line was a negative predictive and prognostic factor.

Predictive factors for skeletal complications in hormone-refractory prostate cancer patients with metastatic bone disease

Factors predictive of skeletal-related events (SREs) in bone metastatic prostate cancer patients with hormone-refractory disease were investigated. We evaluated the frequency of SREs in 200 hormone-refractory patients consecutively observed at our Institution and followed until death or the last follow-up. Baseline parameters were evaluated in univariate and multivariate analysis as potential predictive factors of SREs. Skeletal-related events were observed in 86 patients (43.0%), 10 of which (5.0%) occurred before the onset of hormone-refractory disease. In univariate analysis, patient performance status (P=0.002), disease extent (DE) in bone (P=0.0001), bone pain (P=0.0001), serum alkaline phosphatase (P=0.0001) and urinary N-telopeptide of type one collagen (P=0.0001) directly correlated with a greater risk to develop SREs, whereas Gleason score at diagnosis, serum PSA, Hb, serum albumin, serum calcium, types of bone lesions and duration of androgen deprivation therapy did not. Both DE in bone (hazard ratio (HR): 1.16, 95% confidence interval (CI): 1.07–1.25, P=0.000) and pain score (HR: 1.13, 95% CI: 1.06–1.20, P=0.000) were independent variables predicting for the onset of SREs in multivariate analysis. In patients with heavy tumour load in bone and great bone pain, the percentage of SREs was almost twice as high as (26 vs 52%, P<0.02) and occurred significantly earlier (P=0.000) than SREs in patients with limited DE in bone and low pain. Bone pain and DE in bone independently predict the occurrence of SREs in bone metastatic prostate cancer patients with hormone-refractory disease. These findings could help physicians in tailoring the skeletal follow-up most appropriate to individual patients and may prove useful for stratifying patients enrolled in bisphosphonate clinical trials.

Prognostic significance of disordered calcium metabolism in hormone-refractory prostate cancer patients with metastatic bone disease

Bone metabolic disruption that occurs in bone metastatic prostate cancer could lead to disturbances of calcium metabolism. The prognostic role of either hypocalcemia or hypercalcemia was assessed in a consecutive series of hormone-refractory bone metastatic prostate cancer patients. Serum calcium was measured in 192 patients. The presence of hypocalcemia and hypercalcemia was related with baseline biochemical and clinical characteristics and the role of these two calcium disturbances in predicting prognosis and adverse skeletal-related events (SREs) was assessed. As compared to normocalcemic patients, hypocalcemic patients (n=51) had higher tumor load in bone (P=0.005), higher plasma chromogranin A (CgA, P=0.01), serum alkaline phosphatase (P=0.01), urinary N-telopeptide (NTX, P=0.002) and lower hemoglobin values (P=0.01), while hypercalcemic patients (n=16) had higher plasma CgA (P=0.001) and serum lactate dehydrogenase values (P=0.001), higher bone pain (P=0.003) and a lower frequency of pure osteoblastic lesions (P=0.001). Hypercalcemia was significantly associated with poor prognosis: hazard ratio (HR), 1.9 (95% confidence Interval (CI) 1.2–3.3) and higher risk to develop SREs HR, 2.5 (95% CI 1.2–5.2, P=0.01), while hypocalcemia was not associated with poor prognosis. The prognostic role of hypercalcemia was maintained in multivariate analysis after adjusting for validated prognostic parameters: HR, 2.72 (95% CI 1.1–6.8, P=0.03). These data suggest that serum calcium levels should be taken into account in the clinical decision-making process of bone metastatic prostate cancer patients. Patients with asymptomatic hypercalcemia could benefit of a strict follow-up and an immediate bisphosphonate treatment. Further prospective clinical trials are needed to confirm this finding.

Store-Operated Ca2+Entry Does Not Control Proliferation in Primary Cultures of Human Metastatic Renal Cellular Carcinoma

Store-operated Ca2+ entry (SOCE) is activated following depletion of the inositol-1,4,5-trisphosphate (InsP3)-sensitive Ca2+ pool to regulate proliferation in immortalized cell lines established from either primary or metastatic lesions. The molecular nature of SOCE may involve both Stim1, which senses Ca2+ levels within the endoplasmic reticulum (ER) Ca2+ reservoir, and a number of a Ca2+-permeable channels on the plasma membrane, including Orai1, Orai3, and members of the canonical transient receptor (TRPC1–7) family of ion channels. The present study was undertaken to assess whether SOCE is expressed and controls proliferation in primary cultures isolated from secondary lesions of heavily pretreated metastatic renal cell carcinoma (mRCC) patients. SOCE was induced following pharmacological depletion of the ER Ca2+ store, but not by InsP3-dependent Ca2+ release. Metastatic RCC cells express Stim1-2, Orai1–3, and TRPC1–7 transcripts and proteins. In these cells, SOCE was insensitive to BTP-2, 10 µM Gd3+ and Pyr6, while it was inhibited by 100 µM Gd3+, 2-APB, and carboxyamidotriazole (CAI). Neither Gd3+ nor 2-APB or CAI impaired mRCC cell proliferation. Consistently, no detectable Ca2+ signal was elicited by growth factor stimulation. Therefore, a functional SOCE is expressed but does not control proliferation of mRCC cells isolated from patients resistant to multikinase inhibitors.

Sunitinib, pazopanib or sorafenib for the treatment of patients with late relapsing metastatic renal cell carcinoma.

PURPOSE Late recurrence of renal cell carcinoma is not a rare event. In this retrospective study we investigate the clinicopathological features and the outcome of patients treated with sorafenib, sunitinib and pazopanib for late relapsing renal cell carcinoma. MATERIALS AND METHODS Data were collected from 21 Italian centers involved in the treatment of metastatic renal cell carcinoma. Late relapse was defined as more than 5 years after initial radical nephrectomy. RESULTS A total of 2,490 patients were screened and 269 (11%) were included in the study. First line therapy was sunitinib in 190 patients (71%), sorafenib in 58 (21%) and pazopanib in 21 (8%). Median progression-free survival was 20.0 months for sunitinib (95% CI 17.0-25.1), and 14.1 months for sorafenib (95% CI 11.0-29.0) and pazopanib (95% CI 11.2-not reported). On multivariate analysis MSKCC score and metastases to lymph nodes, liver and brain were associated with worst overall survival, while pancreatic metastases were associated with longer survival. Furthermore, age, MSKCC score and brain metastases were associated with worst progression-free survival. CONCLUSIONS Patients with late relapsing renal cell carcinoma seem to present a characteristic pattern of metastatic spread without showing significant differences in terms of progression-free survival among sorafenib, sunitinib and pazopanib.

Predictors of long-term response to abiraterone in patients with metastastic castration-resistant prostate cancer: A retrospective cohort study

We aimed to identify clinical predictors of long-term response to abiraterone (defined as >12 months drug exposure) in a retrospective cohort of metastatic castration-resistant prostate cancer patients treated in post-docetaxel setting at 24 Italian centers. The Cox proportional hazards model was used to analyze the association between clinical features and the duration of drug exposure. Results were expressed as hazard ratios (HR) with associated 95% confidence intervals (CI). A total of 143 patients met the inclusion criteria. Their median age was 73 years, median Gleason score 8 and median abiraterone exposure 20 months. At the univariate analysis, a significant correlation with the duration of abiraterone exposure was found for Gleason score (HR 0.82, 95% CI 0.71-0.96; p=0.012), PSA (HR 1.10, 95% CI 1.03-1.18; p=0.08) and lactic dehydrogenase levels (HR 1.22, 95% CI 1.02-1.46; p=0.027), while the association between lower alkaline phosphatase levels and treatment duration was marginally significant (HR 1.07, 95% CI 0.99-1.16; p=0.074). Only PSA and Gleason score were predictive of long-term treatment duration in the multivariate analysis. No other clinical factors resulted to be predictive of sustained response to abiraterone, including metastatic disease at diagnosis and visceral disease, suggesting that all subgroups of patients may derive a substantial clinical benefit from abiraterone treatment. These findings need to be validated in prospective, larger studies.

CHANGES IN FREE AND FREE-TO-TOTAL PROSTATE SPECIFIC ANTIGEN AFTER ANDROGEN DEPRIVATION OR CHEMOTHERAPY IN PATIENTS WITH ADVANCED PROSTATE CANCER

PURPOSE To provide preliminary data on whether the diagnostic role of serum prostate specific antigen (PSA) in assessing the response to treatment is improved by concomitant free PSA evaluation both markers were evaluated in 42 patients with advanced prostate cancer who received hormonal therapy and 57 with hormone refractory disease who received chemotherapy. MATERIALS AND METHODS PSA was assessed at baseline and every 3 months during treatment. Free PSA was assessed in stored serum samples obtained at baseline and at maximum PSA decrease. Free PSA was not measurable in 17 patients who received androgen deprivation (40.5%) and 2 who received chemotherapy (3.5%) because it was less than 1.5 ng./ml. RESULTS Of the 21 patients with greater than 50% PSA decrease after hormonal therapy free-to-total PSA increased in 12 (57.2%) and decreased in 9 (42.9%). Of the 20 patients with PSA response after chemotherapy free-to-total PSA increased in 18 (90.0%) and decreased in 2 (10.0%). Free-to-total PSA increased in 12 of the 20 patients (60.0%) with PSA stabilization after chemotherapy. Patients with an increase in free-to-total PSA after chemotherapy had greater survival compared to those with a decrease or no change (19.8 versus 15.5 months, respectively, p <0.03). CONCLUSIONS These data suggest that an effective cytotoxic regimen mainly affects the protein bound PSA fraction. The absence of a clear predominant pattern of free-to-total PSA in patients with PSA response to hormonal therapy and the high percentage of hormone sensitive patients in whom free PSA was not assessable at maximum PSA decrease suggest that free PSA evaluation is less useful in prostate cancer patients undergoing androgen deprivation.

Prognostic Factors in Patients Receiving Third Line Targeted Therapy for Metastatic Renal Cell Carcinoma

PURPOSE Several prognostic models have been proposed for metastatic renal cell carcinoma but none has been validated in patients who receive third line targeted agents. We evaluated prognostic factors in patients with metastatic renal cell carcinoma who received a third line targeted agent. MATERIALS AND METHODS We retrospectively reviewed data on 2,065 patients with clear cell metastatic renal cell carcinoma who were treated with targeted therapy at a total of 23 centers in Italy. Included in final analysis were 281 patients treated with 3 targeted agents. Overall survival was the main outcome. Cox proportional hazards regression followed by bootstrap validation was used to identify independent prognostic factors. RESULTS Three clinical characteristics (ECOG performance status greater than 1, metastasis at diagnosis and liver metastasis) and 2 biochemical factors (hemoglobin less than the lower limit of normal and neutrophil count greater than the upper limit of normal, respectively) were prognostic. Patients were classified into 3 risk categories, including low-zero or 1, intermediate-2 and high risk-more than 2 risk factors. Median overall survival was 19.7, 10.1 and 5.5 months, and 1-year overall survival was 71%, 43% and 15%, respectively. The major limitation was the retrospective nature of this study and absent external validation. CONCLUSIONS This nomogram included clinical and biochemical prognostic factors. In clinical trials it may be useful to select patients and define the prognosis.

Clinical outcome of patients who reduced sunitinib or pazopanib during first-line treatment for advanced kidney cancer

OBJECTIVES To investigate the different outcomes in patients with metastatic renal cell carcinoma (mRCC) who receive a reduced first-line dose of sunitinib or pazopanib compared to those who continue at the standard dose. PATIENTS AND METHODS All the patients treated in 11 oncological centers in Italy for mRCC who started first-line treatment with sunitinib or pazopanib at the standard dose. Descriptive statistical tests were used to highlight differences among groups. Survival was estimated by the Kaplan-Meier method and compared across the groups using log-rank tests, the Cox proportional hazards model adjusted for statistically significant variables was also done. RESULTS A total of 591 patients were included in the study. Of these, 45.7% received a reduced dose of sunitinib or pazopanib after a median treatment time of 3.6 months at the standard dose. The median overall survival in the patients who continued to receive the standard dose was 24.0 months compared to 49.4 months for those who received a reduced dose (hazard ratio = 1.80; 95% CI: 1.42-2.29; P<0.001). Only 45% of the patients received second-line therapy: 42.5% had an mTOR and 54.1% a tyrosine kinase inhibitor. Second-line overall survival was 19.8 and 11.8 months, respectively, in the patients who received, or did not, a reduced dose during first-line therapy (P = 0.007). CONCLUSIONS Toxicity-related dose reduction is a common event in mRCC patients who have started first-line therapy with either sunitinib or pazopanib. This is positively related to the outcomes of both first- and second-line therapy.