Relationship of Metabolic Alterations and PD-L1 Expression in Cisplatin Resistant Lung Cancer.

Despite numerous reports on immune checkpoint inhibitor for the treatment of non-small cell lung cancer (NSCLC), the response rate remains low but durable. Thus cisplatin still plays a major role in the treatment of NSCLC. While there are many mechanisms involved in cisplatin resistance, alteration in metabolic phenotypes with elevated levels of reactive oxygen species (ROS) are found in several cisplatin resistant tumors. These resistant cells become more reliant on mitochondria oxidative metabolism instead of glucose. Consequently, high ROS and metabolic alteration contributed to epithelial-mesenchymal transition (EMT). Importantly, recent findings indicated that EMT has a crucial role in upregulating PD-L1 expression in cancer cells. Thus, it is very likely that cisplatin resistance will lead to high expression of PD-L1/PD-1 which makes them vulnerable to anti PD-1 or anti PD-L1 antibody treatment. An understanding of the interactions between cancer cells metabolic reprogramming and immune checkpoints is critical for combining metabolism targeted therapies with immunotherapies.

Gas6/Axl is the sensor of arginine-auxotrophic response in targeted chemotherapy with arginine-depleting agents.

Many human malignancies lack de novo biosynthesis of arginine (Arg) as the key enzyme argininosuccinate synthetase 1 (ASS1) is silenced. These tumors acquire ectopic Arg for survival, and depleting this source by Arg-depleting recombinant enzyme ADI-PEG20 results in cell death. Mechanisms underlying Arg auxotrophy in these tumors and how they respond to Arg-auxotrophic stress are poorly understood. Here, we report that an immediate-early event of Arg-auxotrophic response involves reactive oxygen species-mediated secretion of Gas6, which interacts with its receptor Axl and activates the downstream Ras/PI3K/Akt growth signal leading to accumulation of c-Myc by protein stabilization. Arg-auxotrophic challenge also transcriptionally upregulates c-Myc expression, which provides a feedback mechanism to enhance Axl expression. c-Myc is a positive regulator of ASS1, but elevated ASS1 provides a feedback mechanism to suppress c-Myc and Axl. Our results revealed multiple inter-regulatory pathways in Arg-auxotrophic response, consisting of Axl, c-Myc and ASS1, which regulate Arg homeostasis and ADI-PEG20 sensitivity. These pathways provide potential targets for improving the efficacy of treating Arg-auxotrophic tumors using Arg-deprivation strategies.

Negative argininosuccinate synthetase expression in melanoma tumours may predict clinical benefit from arginine-depleting therapy with pegylated arginine deiminase.

BACKGROUND: Arginine-depleting therapy with pegylated arginine deiminase (ADI-PEG20) was reported to have activity in advanced melanoma in early phase I-II trial, and clinical trials are currently underway in other cancers. However, the optimal patient population who benefit from this treatment is unknown. METHODS: Advanced melanoma patients with accessible tumours had biopsy performed before the start of treatment with ADI-PEG20 and at the time of progression or relapse when amenable to determine whether argininosuccinate synthetase (ASS) expression in tumour was predictive of response to ADI-PEG20. RESULTS: Twenty-seven of thirty-eight patients treated had melanoma tumours assessable for ASS staining before treatment. Clinical benefit rate (CBR) and longer time to progression were associated with negative expression of tumour ASS. Only 1 of 10 patients with ASS-positive tumours (ASS+) had stable disease, whereas 4 of 17 (24%) had partial response and 5 had stable disease, when ASS expression was negative (ASS-), giving CBR rates of 52.9 vs 10%, P=0.041. Two responding patients with negative ASS expression before therapy had rebiopsy after tumour progression and the ASS expression became positive. The survival of ASS- patients receiving at least four doses at 320 IU m(-2) was significantly better than the ASS+ group at 26.5 vs 8.5 months, P=0.024. CONCLUSION: ADI-PEG20 is safe and the drug is only efficacious in melanoma patients whose tumour has negative ASS expression. Argininosuccinate synthetase tumour positivity is associated with drug resistance and tumour progression.

Arginine deprivation, autophagy, apoptosis (AAA) for the treatment of melanoma.

The majority of melanoma cells do not express argininosuccinate synthetase (ASS), and hence cannot synthesize arginine from citrulline. Their growth and proliferation depend on exogenous supply of arginine. Arginine degradation using arginine deiminase (ADI) leads to growth inhibition and eventually cell death while normal cell which express ASS can survive. This notion has been translated into clinical trial. Pegylated ADI (ADI-PEG20) has shown antitumor activity in melanoma. However, the sensitivity to ADI is different among ASS(-) melanoma cells. We have investigated and reviewed the signaling pathways which are affected by arginine deprivation and their consequences which lead to cell death. We have found that arginine deprivation inhibits mTOR signaling but leads to activation of MEK and ERK with no changes in BRAF. These changes most likely lead to autophagy, a possible mechanism to survive by recycling intracellular arginine. However apoptosis does occur which can be both caspase dependent or independent In order to increase the therapeutic efficacy of this form of treatment, one should consider adding other agent(s) which can drive the cells toward apoptosis or inhibit the autophagic process.

A clinical trial of intravenous vinorelbine tartrate plus tamoxifen in the treatment of patients with advanced malignant melanoma.

BACKGROUND: The aim of the current trial was to assess the efficacy and toxicity of weekly intravenous vinorelbine tartrate with daily oral tamoxifen in the treatment of patients with advanced or metastatic malignant melanoma. METHODS: Thirty-one patients were treated with vinorelbine tartrate, 30 mg/m(2) intravenously, weekly every 13 weeks and then every 2 weeks thereafter until progression of disease or severity of toxicity warranted discontinuation. Tamoxifen, 10 mg orally, twice a day was administered daily starting on Day 1 of chemotherapy with vinorelbine tartrate. Thirty patients had cutaneous melanoma with metastases and 1 patient had ocular melanoma with metastases. Eight patients had received prior chemotherapy. RESULTS: Of the 30 evaluable patients with cutaneous melanoma, 6 achieved a partial response, for an overall response rate of 20% (95% confidence interval, 7-38%). There was no response in the patient with ocular melanoma. Major sites of response include the adrenal gland, lung, tonsil, and cutaneous/subcutaneous tissues. Three patients had a prolonged duration of response lasting > or = 12 months. Side effects generally were mild and tolerable. Grade 3 or 4 hematologic toxicity occurred in 26% and 13% of patients, respectively. Nonhematologic toxicity included mild fatigue, paresthesia, and local arm discomfort from infusion. CONCLUSIONS: Weekly intravenous vinorelbine tartrate plus daily oral tamoxifen appears to be active in the treatment of patients with malignant melanoma. Further clinical trials in malignant melanoma patients treated with vinorelbine tartrate and tamoxifen appear warranted.

A phase I study of chemoembolization with cisplatin, thiotepa, and lipiodol for primary and metastatic liver cancer.

Thirty patients with primary hepatocellular carcinoma or liver metastases were entered into a program of chemoembolization with cisplatin, lipiodol, and escalating doses of thiotepa. Doses of cisplatin were 100/m2, and thiotepa doses ranged from 9 mg/m2 to 24 mg/m2. Two of three patients with ocular melanoma had partial responses in the liver metastases for 3+ and 16 months. In patients with either hepatocellular carcinoma (15 patients) or primary cholangiocarcinoma of the liver (three patients), there were two partial responses, for 22 and 33 months. Five patients had minor responses: four with a 40% reduction in tumor and one with a mixed response. There were four early deaths, which involved sepsis in two patients, respiratory failure in one, and acute myocardial infarction in one. Otherwise, toxicity was tolerable and reversible and included abdominal pain and transient elevation of serum creatinine, bilirubin, and transaminases. Less common toxicities included ototoxicity and peripheral neuropathy. Chemoembolization of the liver with cisplatin, thiotepa, and lipiodol can produce responses, but toxicity can be significant. The recommended starting phase II dose for future studies is thiotepa 24 mg/m2 and cisplatin 100 mg/m2.

A phase II study of intraperitoneal cisplatin and thiotepa in residual ovarian carcinoma: a Gynecologic Oncology Group study.

OBJECTIVE: Patients with advanced epithelial ovarian cancer treated with salvage therapy using new combinations of systemic chemotherapy, radiation therapy, and systemic immunotherapy have had limited success. Since the most common site of relapse or failure to conventional systemic chemotherapy has been the peritoneal cavity, intraperitoneal (IP) chemotherapy was selected to treat small-volume residual disease. METHODS: Sixty-five patients were entered on a protocol using intraperitoneal cisplatin and thiotepa following a response to intravenous cisplatin-based chemotherapy. Patients had surgically documented residual disease (0.5 cm or less maximum tumor diameter) at completion of preprotocol surgery and had no clinical, radiologic, or histologic evidence of extraperitoneal disease. Cisplatin (100 mg/m2) and thiotepa 30 mg/m2 was delivered intraperitoneally every 4 weeks for a maximum of six cycles. The dose of thiotepa was reduced to 12 mg/m2 due to unexpected severe myelosuppression. RESULTS: Of the 52 evaluable patients, grade 4 neutropenia, thrombocytopenia, neurotoxicity, and nephrotoxicity were observed in 31, 19, 13, and 6% of patients, respectively. For all evaluable patients, the complete response rate was 19% and the partial response rate was 2% for a total response rate of 21%. Of 16 patients who had a reassessment laparotomy, 10 patients achieved a surgically documented complete response and 1 patient had a partial response. Four patients are still in response for 67+, 70+, 70+, and 73+ months after third-look surgery. Three patients who did not undergo third-look surgery after chemotherapy are alive and clinically free of disease at 49+, 69+, and 85+ months. CONCLUSION: Thiotepa, when used with cisplatin for IP salvage therapy in patients with advanced or recurrent ovarian cancer, may produce significant myelosuppression and doses must be adjusted accordingly. In cisplatin-sensitive patients with small-volume residual ovarian cancer, IP cisplatin and thiotepa appears to have activity. Determining the utility of this approach will require a randomized trial.

Multidrug-resistant gene expression in small-cell lung cancer.

The development of drug resistance can contribute to treatment failure in small-cell lung cancer (SCLC). In this report, we investigate p-glycoprotein-mediated multidrug resistance (MDR) in these patients. Tumor tissue was obtained prior to treatment and at relapse if possible, short-term culture was carried out, and these tumor cells were analyzed for MDR gene expression by slot blot and reverse transcriptase polymerase chain reaction (RT-PCR) and northern blot analysis. Three cell lines were also established from short-term cultures. Twenty-four patients with MDR(-) and seven with MDR +(++) were available for survival analysis. Median survival for MDR (-) patients was 10 months, whereas for MDR +(++) patients it was 2 months. This was statistically significance (p < 0.0007). The presence of MDR1 gene expression also correlated with the lack of response to chemotherapy (p < 0.001). Increased MDR1 gene expression is usually present in patients with more tumor burden at initial diagnosis. Furthermore, loss of MDR1 gene expression can occur in intrinsically MDR(+) SCLC cells after multiple passages in drug-free media. We concluded that increased MDR1 gene expression is present in a small number of SCLC both before and after chemotherapy and usually signifies poor survival and no response to chemotherapy.

Phase II trial of mitoxantrone and cisplatin in advanced non-small-cell lung cancer.

Because in vitro data suggest that mitoxantrone may be synergistic with cisplatin, a Phase II trial of mitoxantrone and cisplatin was conducted in patients with advanced or metastatic non-small-cell lung cancer (NSLC). Twenty-four patients were evaluable for response. Toxicity was tolerable. Partial response occurred in three patients (13%). This response rate is similar to that reported for cisplatin alone in NSLC. Mitoxantrone did not improve the response rate when combined with cisplatin for patients with advanced NSLC.

Retrospective epidemiologic analysis of patients diagnosed with intracranial meningioma from 1977 to 1990 at the Jackson Memorial Hospital, Sylvester Comprehensive Cancer Center: the Jackson Memorial Hospital Tumor Registry experience.

A descriptive analysis was performed of the Tumor Registry data for intracranial meningioma by the Jackson Memorial Hospital, University of Miami School of Medicine Tumor Registry. A total of 108 cases of intracranial meningioma was collected and reviewed. Overall survival for 2, 5, and 10 years was 82, 72, and 60%, respectively. There was no difference in survival for males and females at 5 years, nor any difference in survival for race or ethnicity. There was a trend for improved survival for the young age group (18-55 years).

Phase II trial of piritrexim and DTIC using an alternating dose schedule in metastatic melanoma.

A Phase II trial was conducted in patients with metastatic malignant melanoma with DTIC 250 mg/m2 intravenously for 5 days alternating monthly with Piritrexim (PTX) using an intermittent, low-dose oral administration schedule. PTX was administered at a starting dose of 25 mg orally three times per day for 5 days weekly for 3 weeks followed by 1 week of rest. Twenty-one patients were entered into the study. Among the 17 patients assessable for response, 1 patient had a minor response, and 3 patients had stable disease. No partial or complete response were observed. Toxicity was tolerable and consistent mainly of myelosuppression. Using this alternating dose schedule, PTX and DTIC produced little response in metastatic melanoma.

Phase II trial of recombinant interferon-alpha with BCNU, cisplatin, DTIC and tamoxifen in advanced malignant melanoma.

Since cytotoxic chemotherapy (BCNU, DTIC and cisplatin, tamoxifen) and interferon-alpha (IFN-alpha) have each produced responses in advanced malignant melanoma, a phase II trial was conducted to evaluate the response and toxicity of simultaneous administration of both therapies. Of 33 assessable patients, two (6%) had complete response (CR) and 12 patients (36%) had partial response (PR), for a total response rate (CR+PR) of 42% (95% confidence interval 26-58). Four patients had minor response (12%). Mixed responses occurred in five patients (15%). The remaining patients had progressive disease. The duration of CR was 3, 7 and 17 (+) months and the duration of PR was 3+ to 19+ months (median 6 months). The median overall survival for all patients entered into the study was 5 months. Main toxicities included myelosuppression and fatigue. Combined simultaneous cytotoxic chemotherapy and IFN produced a high response rate (42%) which is comparable to that reported for chemotherapy alone. Further studies are needed to determine the optimal schedule for combining chemotherapy and immunotherapeutic agents as well as the impact of biological agents on survival in the treatment of melanoma.

A phase II trial of recombinant leukocyte interferon plus doxorubicin in patients with hepatocellular carcinoma.

A Phase II trial of combination therapy with recombinant leukocyte interferon (alpha IFN) and doxorubicin was performed in patients with unresectable hepatocellular carcinoma. alpha IFN was administered at a starting dose of 20 x 10(6) U/m2 intramuscularly or subcutaneously with doxorubicin 20 mg/m2 intravenously weekly x 3 weeks followed by a 2-week period rest. There were 22 patients entered into the study. Among the 21 patients, there were 2 partial responses (10%), one minor response, and one patient had stable disease. Toxicity was generally tolerable, with fever, fatigue, and myelosuppression being the most common side effects. This combination of weekly recombinant leukocytic interferon and doxorubicin has modest and limited activity in hepatocellular carcinoma.

A phase I study of chemoembolization with cisplatin and lipiodol for primary and metastatic liver cancer.

Twenty patients with either unresectable primary hepatocellular carcinoma or hepatic metastases were entered into a chemoembolization program with cisplatin and lipiodol; 19 patients were evaluable for response. Doses of cisplatin ranged from 40 to 100 mg/m2. Toxicity was tolerable and reversible and included abdominal pain, transient elevation in serum creatinine, serum bilirubin, and serum transaminases. Less common side effects include fever, ascites or pleural effusion, and hiccups. Two of four patients with ocular melanoma had partial responses. Duration of response was 10 and 11 months. Among 8 patients with unresectable hepatoma, 2 patients had partial response for 10+ and 13 months, 2 had minor response for 2 months and 4+ months, 1 patient had stable disease for 5+ months, and 3 patients failed to respond. Of the six colon cancer patients treated, one had a partial response in the liver, but developed progressive nodal disease, and another patient had a partial response for 3 months. Chemoembolization of the liver with cisplatin and lipiodol is feasible and doses of cisplatin at least 100 mg/m2 are tolerable. Antitumor activity in metastatic ocular melanoma is encouraging but requires further study.

Oral piritrexim in advanced bladder cancer: an effective drug after progression on MVAC chemotherapy?

Four patients with advanced or metastatic bladder cancer progressing after MVAC chemotherapy were treated with oral piritrexim. Three of the four patients were evaluable for response, and all three had a partial response to treatment. Piritrexim may be an effective drug for bladder cancer after progression on MVAC chemotherapy.

The role of steroids in the management of metastatic carcinoma to the brain. A pilot prospective trial.

This prospective study attempted to evaluate the indications for glucocorticoids which are commonly given to patients with brain metastases. Twelve patients with histologically confirmed malignancies and radiographically documented brain metastases were enrolled. Patients were scored for general performance status and neurologic function class. All subjects were given high-dose dexamethasone (HDD) for 48 hours and then randomized to receive either intermediate-dose dexamethasone (IDD) or no steroids with cranial radiotherapy. Of these 12 study patients, 3 achieved a complete response, 1 partial response, and 8 nonresponses to HDD. Seven patients had IDD, while five received no IDD. Although a small sample size prevented any statistical analysis, this study does suggest that the place for using glucocorticoids in treating patients with metastatic carcinoma to the brain remains uncertain and should be evaluated in a cooperative prospective trial.

Melanoma in a southeastern Hispanic population.

A descriptive analysis was performed of the Tumor Registry data for malignant melanoma in Hispanics ascertained by the Jackson Memorial Hospital (JMH), University of Miami School of Medicine Tumor Registry. A total of 54 cases of melanoma in Hispanics was collected and reviewed. Most of the lesions of melanoma occurred on the trunk, arm, shoulder, leg, and hip. Seventy percent of the Hispanics presented with local stage disease; 26% presented with both regional and distant disease. Local stage had the best 5-year survival (87%). In regional and distant disease combined, the survival was better for Hispanics than non-Hispanics (p = 0.01). In addition, it was found that the Hispanics in the over 50-year-old age group did better than the non-Hispanics in the same group (p = 0.05). Comparison of survival between Hispanic males and females shows that Hispanic females have a 5-year survival of 86% compared to 56% for Hispanic males (p = 0.017).

Drug resistance in brain tumors.

Resistance to chemotherapy in brain tumors is complex and may involve multiple mechanisms. For commonly used drugs, such as nitrosoureas and platinum compounds, major mechanisms may involve increaded DNA repair or removal of the drug-DNA adducts. For water soluble nitrosoureas and also for platinum compounds, other mechanisms, such as alteration in drug transport, may be important. Another major mechanism may involve glutathione and glutathione-S-transferase pathways. For vinca alkaloids and epipodophyllotoxins p-glycoprotein mediated MDR appears to be the major feature in drug resistance. In addition, alteration of tubulin and topoisomerase II have been described in resistance to vinca alkaloids and epipodophyllotoxins respectively. Recently, increased multidrug resistance associated protein gene expression has been found in glioma cells and brain tumor samples; its clinical significance requires further investigation.

A phase II trial of tricyclic nucleoside phosphate in patients with advanced squamous cell carcinoma of the cervix. A Gynecologic Oncology Group Study.

A Phase II trial of TCN-P was conducted in metastatic or recurrent squamous cell carcinoma of the cervix using a 5-day continuous infusion schedule. The starting dose was 35 mg/m2 x 5 days and courses were repeated every 6 weeks. Among 21 evaluable patients, 2 responses were observed. One patient had a complete response for 19+ months. Another patient had a partial response for 5+ months, but developed symptomatic hypocalcemia, requiring discontinuation of the drug. Using this dose and schedule TCN-P appears to have limited activity in metastatic or recurrent squamous cell cancer of the cervix.