Richard C. Lauer

Salvage Therapy in Recurrent Germ Cell Cancer: Ifosfamide and Cisplatin plus Either Vinblastine or Etoposide

STUDY OBJECTIVE To determine the efficacy of the addition of ifosfamide to cisplatin plus etoposide (VIP), or vinblastine (VeIP), in patients with recurrent germ cell tumors. DESIGN Nonrandomized, prospective phase II trial. SETTING Tertiary referral university hospital. PATIENTS Fifty-six of fifty-eight entered patients with measurable and progressive recurrent germ cell tumors of testicular (46 patients), ovarian (1 patient), and extragonadal (9 patients) origin were evaluable for response after not being cured with cisplatin, vinblastine, and etoposide regimens. INTERVENTIONS Patients were administered cisplatin (20 mg/m2 body surface area daily for 5 days), ifosfamide (1.2 g daily for 5 days), plus either etoposide (75 mg daily for 5 days) or vinblastine (0.11 mg/kg body weight on days 1 and 2). In addition, vigorous intravenous hydration therapy with normal saline (100 to 125 mL/h) was administered during the treatment course. Uroepithelial protective agents, N-acetylcysteine (orally) or mesna (intravenously), were administered. Four courses were administered to responding patients every 3 weeks. When complete excision was feasible, surgical resection of residual tumor was done approximately 6 to 8 weeks after chemotherapy. MEASUREMENTS AND MAIN RESULTS Twelve of fifty-six evaluable patients had a complete remission with chemotherapy alone, whereas 8 additional patients were free of disease after resection of teratoma (3 patients) or carcinoma (5 patients) for a total disease-free rate of 36% (95% CI, 23.4 to 49.6). The 95% CI median duration of remission for these patients is 34 months (range, 3 to more than 42; 95% CI, 9 months to infinity), and the median survival for all eligible patients is 12.7 months (95% CI, 10 months to 26 months), with 15 of the 20 patients who achieved disease-free status alive 18 to 53 months or more. Nine of fifty-eight patients remain free of disease, including 7 patients for 2 years or longer. Hematologic and nephrotoxicity were the predominant drug-related toxicities, with one drug-related death secondary to pneumonia. CONCLUSIONS Ifosfamide combination chemotherapy as third-line or greater therapy can produce durable complete remissions in heavily pretreated patients with recurrent germ cell tumors.

Is prophylactic cranial irradiation indicated in small-cell lung cancer?

Although prophylactic cranial irradiation (PCI) is frequently used in the treatment of patients with limited-extent small-cell lung cancer (SCLC), its role remains controversial. One hundred fourteen SCLC patients with limited disease treated at Indiana University were retrospectively reviewed. Fifty-eight of 114 (51%) patients achieved a complete remission (CR) and were analyzed. Thirty-eight of these 58 CR patients received PCI (+PCI) and 20 of 58 CR patients did not receive PCI (-PCI). Twenty-six of 38 patients who received PCI subsequently relapsed. No patient initially relapsed in the CNS, although one patient had a brain metastasis following recurrence in the chest. Eleven of 38 patients who were treated with PCI survived for longer than 30 months and were considered long-term survivors. Seven of these 11 patients (63%) developed clinically significant neurological toxicity. Sixteen of 20 patients who did not receive PCI relapsed, but there was only one initial relapse in the CNS. Three additional patients who relapsed in the chest subsequently developed CNS metastasis. All responded to palliative radiation with improvement in their symptoms. The high incidence of CNS toxicity in the long-term survivors and the relatively infrequent incidence of isolated CNS recurrent in patients not subjected to PCI raise serious questions concerning the role, if any, of PCI in limited SCLC.

PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3.

Significance Prostate cancer has an unpredictable natural history: While most tumors are clinically indolent, some patients display lethal phenotypes. Serum prostate-specific antigen is the most often used test in prostate cancer but screening is controversial. Treatment options are limited for metastatic disease, hence the need for early diagnosis. Prostate cancer antigen 3 (PCA3), a long noncoding RNA, is the most specific biomarker identified and approved as a diagnostic test. However, its inherent biological function (if any) has remained elusive. We uncovered a negative transdominant oncogenic role for PCA3 that down-regulates an unrecognized tumor suppressor gene, PRUNE2 (a human homolog of the Drosophila prune gene) thereby promoting malignant cell growth. This work defines a unique biological function for PCA3 in prostate cancer. Prostate cancer antigen 3 (PCA3) is the most specific prostate cancer biomarker but its function remains unknown. Here we identify PRUNE2, a target protein-coding gene variant, which harbors the PCA3 locus, thereby classifying PCA3 as an antisense intronic long noncoding (lnc)RNA. We show that PCA3 controls PRUNE2 levels via a unique regulatory mechanism involving formation of a PRUNE2/PCA3 double-stranded RNA that undergoes adenosine deaminase acting on RNA (ADAR)-dependent adenosine-to-inosine RNA editing. PRUNE2 expression or silencing in prostate cancer cells decreased and increased cell proliferation, respectively. Moreover, PRUNE2 and PCA3 elicited opposite effects on tumor growth in immunodeficient tumor-bearing mice. Coregulation and RNA editing of PRUNE2 and PCA3 were confirmed in human prostate cancer specimens, supporting the medical relevance of our findings. These results establish PCA3 as a dominant-negative oncogene and PRUNE2 as an unrecognized tumor suppressor gene in human prostate cancer, and their regulatory axis represents a unique molecular target for diagnostic and therapeutic intervention.

KRAS2 oncogene overexpression in myelodysplastic syndrome with translocation 5;12

The factors that initiate and maintain the abnormal hematopoietic clone in the myelo-dysplastic syndromes (MDS) remain largely unknown. We describe a patient with MDS associated with an abnormal karyotype, 46,XY,t(5;12)(q31;p12). According to the FAB cooperative group classification, the patient was classified as chronic myelomonocytic leukemia. Because of the particular chromosomal translocation, the structure-function relationship of three genes relevant to the translocation breakpoints, CSF2, FMS, and KRAS2, was studied in bone marrow and peripheral blood lymphocytes in this patient. No major structural alterations were observed at these three genetic loci. Although the levels of expression of the CSF2 and FMS genes remained unaltered, the KRAS2 oncogene was overexpressed approximately six-fold in bone marrow cells from the MDS patient compared with normal donors. We postulate that the RAS oncogene activation may be instrumental in the genesis of MDS.

A Phase I/II Trial of BNC105P with Everolimus in Metastatic Renal Cell Carcinoma

Purpose: BNC105P inhibits tubulin polymerization, and preclinical studies suggest possible synergy with everolimus. In this phase I/II study, efficacy and safety of the combination were explored in patients with metastatic renal cell carcinoma (mRCC). Experimental Design: A phase I study in patients with clear cell mRCC and any prior number of therapies was conducted using a classical 3 + 3 design to evaluate standard doses of everolimus with increasing doses of BNC105P. At the recommended phase II dose (RP2D), patients with clear cell mRCC and one to two prior therapies (including ≥ 1 VEGF-TKI) were randomized to BNC105P with everolimus (arm A) or everolimus alone (arm B). The primary endpoint of the study was 6-month progression-free survival (6MPFS). Secondary endpoints included response rate, PFS, overall survival, and exploratory biomarker analyses. Results: In the phase I study (N = 15), a dose of BNC105P at 16 mg/m2 with everolimus at 10 mg daily was identified as the RP2D. In the phase II study, 139 patients were randomized, with 69 and 67 evaluable patients in arms A and B, respectively. 6MPFS was similar in the treatment arms (arm A: 33.82% vs. arm B: 30.30%, P = 0.66) and no difference in median PFS was observed (arm A: 4.7 mos vs. arm B: 4.1 mos; P = 0.49). Changes in matrix metalloproteinase-9, stem cell factor, sex hormone-binding globulin, and serum amyloid A protein were associated with clinical outcome with BNC105P. Conclusions: Although the primary endpoint was not met in an unselected population, correlative studies suggest several biomarkers that warrant further prospective evaluation. Clin Cancer Res; 21(15); 3420–7. ©2015 AACR.

Targeted molecular-genetic imaging and ligand-directed therapy in aggressive variant prostate cancer

Significance Aggressive variant prostate cancer (AVPC) is a clinically defined tumor with neuroendocrine or small-cell differentiation, visceral metastases, low prostate-specific antigen, androgen receptor insensitivity, and poor/brief responses to androgen-deprivation or platinum-based chemotherapy. AVPC incidence has markedly increased, yielding an unmet diagnostic/therapeutic need. Here we adapted a patient-derived xenograft model and tumor samples to demonstrate ligand-directed theranostics of AVPC in vivo. We engineered human Herpes simplex virus thymidine kinase type-1 as a noninvasive imaging reporter/suicide transgene into adeno-associated virus/phage (AAVP) particles displaying motif ligands to cell surface-associated glucose-regulated protein 78kD (GRP78), toward a clinic-ready system. Although individual components of the AAVP system have been extensively investigated, this study is evidence of successful application in relevant preclinical models of untreatable and hard to diagnose aggressive tumor variants. Aggressive variant prostate cancers (AVPC) are a clinically defined group of tumors of heterogeneous morphologies, characterized by poor patient survival and for which limited diagnostic and treatment options are currently available. We show that the cell surface 78-kDa glucose-regulated protein (GRP78), a receptor that binds to phage-display-selected ligands, such as the SNTRVAP motif, is a candidate target in AVPC. We report the presence and accessibility of this receptor in clinical specimens from index patients. We also demonstrate that human AVPC cells displaying GRP78 on their surface could be effectively targeted both in vitro and in vivo by SNTRVAP, which also enabled specific delivery of siRNA species to tumor xenografts in mice. Finally, we evaluated ligand-directed strategies based on SNTRVAP-displaying adeno-associated virus/phage (AAVP) particles in mice bearing MDA-PCa-118b, a patient-derived xenograft (PDX) of castration-resistant prostate cancer bone metastasis that we exploited as a model of AVPC. For theranostic (a merging of the terms therapeutic and diagnostic) studies, GRP78-targeting AAVP particles served to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) gene, which has a dual function as a molecular-genetic sensor/reporter and a cell suicide-inducing transgene. We observed specific and simultaneous PET imaging and treatment of tumors in this preclinical model of AVPC. Our findings demonstrate the feasibility of GPR78-targeting, ligand-directed theranostics for translational applications in AVPC.

Drug design strategies for the treatment of prostate cancer

Introduction: While metastatic prostate cancer remains an incurable tumor, remarkable progress has been made with novel drug design strategies for this incurable disease. Several new agents, including hormonal analogues, cytotoxic chemotherapy drugs, radionuclides and innovative targeted therapies, have recently been approved by the FDA for use in advanced and/or metastatic castrate-resistant prostate cancer. Furthermore, a growing number of new diagnostic or predictive genetic tests have also been incorporated into the management of this disease. Immunotherapy-based approaches have shown promise and have led to drug approvals. Other experimental approaches such as vascular targeting are in early translational clinical trials. Areas covered: Herein, the authors outline select state-of-the-art approaches in the field. They also discuss the current challenges and future opportunities in the medical care of prostate cancer patients. Expert opinion: An inherent challenge in the treatment of prostate cancer is to determine which patients need immediate aggressive treatment versus active surveillance. For patients needing aggressive treatment, integrating the sequence of therapeutic interventions, to provide the most benefit, remains a challenge that clinicians face. Recently, several genetic tests have been approved, facilitating early treatment decisions. Innovative targeted therapies are moving towards clinical applications, providing treatment options for tumors previously considered refractory to androgen ablation treatment.

A variant t(X;15)(p11;q22) translocation in acute promyelocytic leukemia

Nonrandom reciprocal translocations involving chromosomes #15 and #17 are characteristic anomalies in a great majority of cases of acute promyelocytic leukemia (APL). Other complex translocations in APL that invariably involve chromosome #17 also have been described. We describe a patient with clinical and morphologic characteristics of APL but with a previously undescribed acquired karyotype, t(X;15)(p11;q22). This is the first translocation in APL described in which chromosome #17 is not involved. Although a comparative structure/function analysis of potentially relevant genes to the translocation breakpoints in both t(X;15) and t(15;17) APL showed no major alterations, the enhanced expression of the c-Ki-ras oncogene observed in t(X;15) APL supports the concept of heterogeneity in APL at the cytogenetic and molecular levels.

Phase II Study of Sorafenib and Bortezomib for First-Line Treatment of Metastatic or Unresectable Renal Cell Carcinoma

BACKGROUND Sorafenib is an orally active multikinase inhibitor, and bortezomib is a proteasome inhibitor that affects multiple signaling pathways. Sorafenib has clinical activity in renal cell carcinoma (RCC), whereas bortezomib has demonstrated activity against RCC cell lines in vitro, with in vitro studies showing synergism between the two agents in the induction of apoptosis in neoplastic cell lines. In this phase II study, we explored the efficacy and toxicity of this regimen. METHODS Adult patients with cytologically confirmed clear cell RCC with no prior chemotherapy, Zubrod performance status of 0-1, serum creatinine <1.5 mg/dL, and normal liver function tests were treated with sorafenib 200 mg orally b.i.d. with bortezomib 1 mg/m(2) intravenously on days 1, 4, 8, and 11 every 21 days. Treatment was continued until disease progression or unacceptable toxicity. The primary objective was median progression-free survival (PFS) of at least 70 weeks. RESULTS Seventeen patients were enrolled between April 2011 and January 2013. Median age was 62 years (range: 44-75 years). Four of 17 patients had known brain metastasis on enrollment. Median number of cycles was 4 (range: 1 to ≥45). No patient had complete response, 1 had partial response, 12 had stable disease, and 4 had progressive disease (response rate of 6%; 95% confidence interval: 0%-29%) with treatment. Median PFS was 13.7 weeks, and median overall survival was 110 weeks. The study was halted for futility. CONCLUSION The combination of sorafenib and bortezomib was well tolerated; however, response rate and PFS were comparable to sorafenib monotherapy. This regimen is not recommended for further development.

Phase I/II study of a BNC105P/everolimus regimen for progressive metastatic renal cell carcinoma (mRCC) following prior tyrosine kinase inhibitors (Hoosier Oncology Group).

373 Background: BNC105P is a Vascular Disruption Agent (VDA) that destabilizes tubulin polymers leading to selective damage of tumor vasculature, hypoxia and associated tumor necrosis. BNC105P also has a direct anti-proliferative action on cancer cells. Up regulation of the mTOR pathway has been identified as a survival response by the tumor to hypoxic insult. Preclinical investigations demonstrated that BNC105P is effective at selectively damaging the vasculature in primary and metastatic lesions. Furthermore, BNC105P monotherapy compared well with sunitinib in mice bearing kidney tumors. It follows that the combined use of this VDA with an agent active against mTOR may improve clinical outcome in patients with progressive mRCC who are refractory to tyrosine kinase inhibitors (TKI). METHODS A phase I/II study in mRCC patients who have received 1-2 prior TKIs was undertaken. Using a classic 3+3 design, the phase I component of this study enrolled 12 subjects at 4 dose levels of BNC105P (4.2, 8.4, 12.6 and 16 mg/m2; IV infusion Days 1 & 8, 21-day repeating cycle). Everolimus was administered concurrently (10 mg p.o.). PK analysis was performed during Cycle 1. RESULTS In the clinic the BNC105P / everolimus combination was well tolerated and no DLTs were observed in any of the phase I patients. Toxicities deemed to be drug-related included single events of Grade 2 anemia, thrombocytopenia and mucositis. Of the 12 patients enrolled to the phase I, 7 remain on treatment. The medium number of cycles is 3 (range: 1-14) and 3 patients have been administered >6 cycles of treatment. The randomized phase II component of the study continues and will compare everolimus given in combination with BNC105P to a sequential approach (everolimus followed by BNC105P). CONCLUSIONS The MTD of BNC105P (16 mg/m2) can be combined with full dose everolimus and is being evaluated in the randomized phase II study.