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Gullbo, Joachim
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Mody, K., Mansfield, A. S., Vemireddy, L., Nygren, P., Gullbo, J. & Borad, M. (2019). A phase I study of the safety and tolerability of VLX600, an Iron Chelator, in patients with refractory advanced solid tumors. Investigational new drugs, 37(4), 684-692
Öppna denna publikation i ny flik eller fönster >>A phase I study of the safety and tolerability of VLX600, an Iron Chelator, in patients with refractory advanced solid tumors
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2019 (Engelska)Ingår i: Investigational new drugs, ISSN 0167-6997, E-ISSN 1573-0646, Vol. 37, nr 4, s. 684-692Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Introduction VLX600 is a novel iron chelator designed to interfere with intracellular iron metabolism, leading to inhibition of mitochondrial respiration and bioenergetic catastrophe and resultant tumor cell death. Methods We conducted a multicenter, phase 1, dose escalation study to determine the safety and adverse event profile and the maximum tolerated dose and recommended phase 2 dose of VLX600. Other endpoints included pharmacokinetics, and preliminary evidence of anti-cancer efficacy as assessed according to RECIST 1.1 criteria. VLX600 was administered intravenously on days 1, 8, and 15 of each 28-day treatment cycle. Results Nineteen patients were enrolled, and seventeen received at least one dose of VLX600. Dose increments were reduced to 50% after dose level 3 (40mg) due to the occurrence of a grade 3 pulmonary embolism. The study was then closed early due to slow recruitment. No maximum tolerated dose (MTD) nor RP2D had been identified at the time of study closure. Overall, the drug was well tolerated and no DLTs were observed. Fourteen patients experienced drug-related adverse events of any grade. The most frequently reported drug-related AEs were fatigue, nausea, constipation, vomiting, increased alkaline phosphatase, anemia, and decreased appetite. No formal efficacy or survival analyses were performed. No objective responses were observed, though six patients (32%) had stable disease as best response. Conclusion VLX600 was reasonably well tolerated and, together with preclinical data, there is support for further efforts to explore its activity as single agent and in combination with drugs or radiation.

Ort, förlag, år, upplaga, sidor
SPRINGER, 2019
Nyckelord
Clinical trial, Phase 1, Iron chelating agents, VLX600
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:uu:diva-390390 (URN)10.1007/s10637-018-0703-9 (DOI)000475627500010 ()30460505 (PubMedID)
Tillgänglig från: 2019-08-09 Skapad: 2019-08-09 Senast uppdaterad: 2019-08-09Bibliografiskt granskad
Lindman, H., Nilsson, A. & Gullbo, J. (2017). Clinical characteristics of CNS metastases of different breast cancer subtypes - Results from a cohort study. Paper presented at San Antonio Breast Cancer Symposium, DEC 06-10, 2016, San Antonio, TX. Cancer Research, 77
Öppna denna publikation i ny flik eller fönster >>Clinical characteristics of CNS metastases of different breast cancer subtypes - Results from a cohort study
2017 (Engelska)Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77Artikel i tidskrift (Refereegranskat) Published
Ort, förlag, år, upplaga, sidor
AMER ASSOC CANCER RESEARCH, 2017
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:uu:diva-320980 (URN)10.1158/1538-7445.SABCS16-P1-12-09 (DOI)000397999000290 ()
Konferens
San Antonio Breast Cancer Symposium, DEC 06-10, 2016, San Antonio, TX
Tillgänglig från: 2017-04-27 Skapad: 2017-04-27 Senast uppdaterad: 2017-04-27Bibliografiskt granskad
Delforoush, M., Berglund, M., Edqvist, P.-H., Sundström, C., Gullbo, J. & Enblad, G. (2017). Expression of possible targets for new proteasome inhibitors in diffuse large B-cell lymphoma. European Journal of Haematology, 98(1), 52-56
Öppna denna publikation i ny flik eller fönster >>Expression of possible targets for new proteasome inhibitors in diffuse large B-cell lymphoma
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2017 (Engelska)Ingår i: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 98, nr 1, s. 52-56Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Objectives: Investigating expression of possible targets for proteasome inhibitors in patients with diffuse large B-cell lymphoma (DLBCL) and correlating the findings to clinical parameters and outcome.

Methods: Tumour material from 92 patients with DLBCL treated with either R-CHOP like (n = 69) or CHOP like (n = 23) regimens were stained for possible targets of proteasome inhibitors.

Results: The primary target molecule of bortezomib, proteasome subunit beta, type 5 (PSMB5), was not detected in the tumour cells in any of the cases but showed an abundant expression in cells in the microenvironment. However, the deubiquitinases (DUBs) of the proteasome, the ubiquitin carboxyl-terminal hydrolase L5 (UCHL5) and the ubiquitin specific peptidase 14 (USP14), were detected in the cytoplasm of the tumour cells in 77% and 74% of the cases, respectively. The adhesion regulating molecule 1 (ADRM1) was detected in 98% of the cases. There was no correlation between the expression of any of the studied markers and clinical outcome or GC/non-GC phenotype.

Conclusions: We suggest that UCHL5 and/or USP14 should be further evaluated as new targets for proteasome inhibitors in DLBCL. The lack of expression of PSMB5 on the tumour cells might provide an explanation of the relatively poor results of bortezomib in DLBCL.

Nyckelord
proteasome inhibitors, UCHL5, USP14
Nationell ämneskategori
Medicin och hälsovetenskap Cancer och onkologi
Identifikatorer
urn:nbn:se:uu:diva-280542 (URN)10.1111/ejh.12784 (DOI)000393166600008 ()27301795 (PubMedID)
Forskningsfinansiär
Cancerfonden
Tillgänglig från: 2016-03-11 Skapad: 2016-03-11 Senast uppdaterad: 2017-11-30Bibliografiskt granskad
Strese, S., Hassan, S. B., Velander, E., Haglund, C., Höglund, M., Larsson, R. & Gullbo, J. (2017). In vitro and in vivo anti-leukemic activity of the peptidase-potentiated alkylator melflufen in acute myeloid leukemia. OncoTarget, 8(4), 6341-6352
Öppna denna publikation i ny flik eller fönster >>In vitro and in vivo anti-leukemic activity of the peptidase-potentiated alkylator melflufen in acute myeloid leukemia
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2017 (Engelska)Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 4, s. 6341-6352Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The novel aminopeptidase potentiated alkylating agent melflufen, was evaluated for activity in acute myeloid leukemia in a range of in vitro models, as well as in a patient derived xenograft study. All tested AML cell lines were highly sensitive to melflufen while melphalan was considerably less potent. In the HL-60 cell line model, synergy was observed for the combination of melflufen and cytarabine, an interaction that appeared sequence dependent with increased synergy when melflufen was added before cytarabine. Also, in primary cultures of AML cells from patients melflufen was highly active, while normal PBMC cultures appeared less sensitive, indicating a 7-fold in vitro therapeutic index. Melphalan, on the other hand, was only 2-fold more potent in the AML patient samples compared with PBMCs. Melflufen was equally active against non-malignant, immature CD34(+) progenitor cells and a more differentiated CD34(+) derived cell population (GM14), whereas the stem cell like cells were less sensitive to melphalan. Finally, melflufen treatment showed significant anti-leukemia activity and increased survival in a patient derived xenograft of AML in mice. In conclusion, melflufen demonstrates high and significant preclinical activity in AML and further clinical evaluation seem warranted in this disease.

Nyckelord
melflufen, drug development, alkylator, pre-clinical, acute myeloid leukemia
Nationell ämneskategori
Cancer och onkologi Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:uu:diva-317697 (URN)10.18632/oncotarget.13856 (DOI)000393289000079 ()27974676 (PubMedID)
Tillgänglig från: 2017-03-17 Skapad: 2017-03-17 Senast uppdaterad: 2018-02-26Bibliografiskt granskad
Karlsson, H., Fryknäs, M., Strese, S., Gullbo, J., Westman, G., Bremberg, U., . . . Nygren, P. (2017). Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity. OncoTarget, 8(18), 30217-30234
Öppna denna publikation i ny flik eller fönster >>Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity
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2017 (Engelska)Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 18, s. 30217-30234Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background: The thiosemicarbazone CD 02750 (VLX50) was recently reported as a hit compound in a phenotype-based drug screen in primary cultures of patient tumor cells. We synthesized a copper complex of VLX50, denoted VLX60, and characterized its antitumor and mechanistic properties.

Materials and Methods: The cytotoxic effects and mechanistic properties of VLX60 were investigated in monolayer cultures of multiple human cell lines, in tumor cells from patients, in a 3-D spheroid cell culture system and in vivo and were compared with those of VLX50.

Results: VLX60 showed >= 3-fold higher cytotoxic activity than VLX50 in 2-D cultures and, in contrast to VLX50, retained its activity in the presence of additional iron. VLX60 was effective against non-proliferative spheroids and against tumor xenografts in vivo in a murine model. In contrast to VLX50, gene expression analysis demonstrated that genes associated with oxidative stress were considerably enriched in cells exposed to VLX60 as was induction of reactive oxygen. VLX60 compromised the ubiquitin-proteasome system and was more active in BRAF mutated versus BRAF wild-type colon cancer cells.

Conclusions: The cytotoxic effects of the copper thiosemicarbazone VLX60 differ from those of VLX50 and shows interesting features as a potential antitumor drug, notably against BRAF mutated colorectal cancer.

Ort, förlag, år, upplaga, sidor
IMPACT JOURNALS LLC, 2017
Nyckelord
cancer drug, thiosemicarbazone, spheroid, VLX60, BRAF
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:uu:diva-323035 (URN)10.18632/oncotarget.16324 (DOI)000400456200055 ()28415818 (PubMedID)
Forskningsfinansiär
CancerfondenStiftelsen för strategisk forskning (SSF)
Tillgänglig från: 2017-06-01 Skapad: 2017-06-01 Senast uppdaterad: 2017-11-29Bibliografiskt granskad
Wickström, M., Nygren, P., Larsson, R., Harmenberg, J., Lindberg, J., Sjoberg, P., . . . Gullbo, J. (2017). Melflufen: a peptidase-potentiated alkylating agent in clinical trials. OncoTarget, 8(39), 66641-66655
Öppna denna publikation i ny flik eller fönster >>Melflufen: a peptidase-potentiated alkylating agent in clinical trials
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2017 (Engelska)Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 39, s. 66641-66655Artikel, forskningsöversikt (Refereegranskat) Published
Abstract [en]

Aminopeptidases like aminopeptidase N (APN, also known as CD13) play an important role not only in normal cellular functioning but also in the development of cancer, including processes like tumor cell invasion, differentiation, proliferation, apoptosis, motility, and angiogenesis. An increased expression of APN has been described in several types of human malignancies, especially those characterized by fast-growing and aggressive phenotypes, suggesting APN as a potential therapeutic target. Melphalan flufenamide ethyl ester (melflufen, previously denoted J1) is a peptidase-potentiated alkylating agent. Melflufen readily penetrates membranes and an equilibrium is rapidly achieved, followed by enzymatic cleavage in aminopeptidase positive cells, which results in trapping of less lipophilic metabolites. This targeting effect results in very high intracellular concentrations of its metabolite melphalan and subsequent apoptotic cell death. This results in a potency increase (melflufen vs melphalan) ranging from 10- to several 100-fold in different in vitro models. Melflufen triggers a rapid, robust, and an irreversible DNA damage which may account for its ability to overcome melphalan-resistance in multiple myeloma cells. Furthermore, anti-angiogenic properties of melflufen have been described. Consequently, it is hypothesized that melflufen could provide better efficacy but no more toxicity than what is achieved with melphalan, an assumption so far supported by experiences from hollow fiber and xenograft studies in rodents as well as by clinical data from patients with solid tumors and multiple myeloma. This review summarizes the current preclinical and clinical knowledge of melflufen.

Ort, förlag, år, upplaga, sidor
IMPACT JOURNALS LLC, 2017
Nyckelord
melflufen, aminopeptidase, cancer, targeted chemotherapy
Nationell ämneskategori
Cancer och onkologi Farmakologi och toxikologi
Identifikatorer
urn:nbn:se:uu:diva-346504 (URN)10.18632/oncotarget.18420 (DOI)000410291200163 ()29029544 (PubMedID)
Tillgänglig från: 2018-03-19 Skapad: 2018-03-19 Senast uppdaterad: 2018-03-19Bibliografiskt granskad
Eriksson, A., Chantzi, E., Fryknäs, M., Gullbo, J., Nygren, P., Gustafsson, M. G., . . . Larsson, R. (2017). Towards repositioning of quinacrine for treatment of acute myeloid leukemia - Promising synergies and in vivo effects.. Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, 63, 41-46
Öppna denna publikation i ny flik eller fönster >>Towards repositioning of quinacrine for treatment of acute myeloid leukemia - Promising synergies and in vivo effects.
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2017 (Engelska)Ingår i: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 63, s. 41-46Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

We previously reported that the anti-malarial drug quinacrine has potential to be repositioned for treatment of acute myeloid leukemia (AML). As a next step towards clinical use, we assessed the efficacy of quinacrine in an AML-PS mouse model and investigated possible synergistic effects when combining quinacrine with nine other antileukemic compounds in two AML cell lines. Furthermore, we explored the in vivo activity of quinacrine in combination with the widely used AML agent cytarabine. The in vivo use of quinacrine (100mg/kg three times per week for two consecutive weeks) significantly suppressed circulating blast cells at days 30/31 and increased the median survival time (MST). The in vitro drug combination analysis yielded promising synergistic interactions when combining quinacrine with cytarabine, azacitidine and geldanamycin. Finally, combining quinacrine with cytarabine in vivo showed a significant decrease in circulating leukemic blast cells and increased MST compared to the effect of either drug used alone, thus supporting the findings from the in vitro combination experiments. Taken together, the repositioning potential of quinacrine for treatment of AML is reinforced by demonstrating significant in vivo activity and promising synergies when quinacrine is combined with different agents, including cytarabine, the hypomethylating agent azacitidine and HSP-90 inhibitor geldanamycin.

Nyckelord
Acute myeloid leukemia, Drug combinations, Quinacrine, Repositioning
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:uu:diva-342993 (URN)10.1016/j.leukres.2017.10.012 (DOI)000416744700007 ()29100024 (PubMedID)
Tillgänglig från: 2018-02-24 Skapad: 2018-02-24 Senast uppdaterad: 2018-03-01Bibliografiskt granskad
Delforoush, M., Strese, S., Wickström, M., Larsson, R., Enblad, G. & Gullbo, J. (2016). In vitro and in vivo activity of melflufen (J1) in lymphoma. BMC Cancer, 16, Article ID 263.
Öppna denna publikation i ny flik eller fönster >>In vitro and in vivo activity of melflufen (J1) in lymphoma
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2016 (Engelska)Ingår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 16, artikel-id 263Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background: Melphalan has been used in the treatment of various hematologic malignancies for almost 60 years. Today it is part of standard therapy for multiple myeloma and also as part of myeloablative regimens in association with autologous allogenic stem cell transplantation. Melflufen (melphalan flufenamide ethyl ester, previously called J1) is an optimized derivative of melphalan providing targeted delivery of active metabolites to cells expressing aminopeptidases. The activity of melflufen has compared favorably with that of melphalan in a series of in vitro and in vivo experiments performed preferentially on different solid tumor models and multiple myeloma. Melflufen is currently being evaluated in a clinical phase I/II trial in relapsed or relapsed and refractory multiple myeloma.

Methods: Cytotoxicity of melflufen was assayed in lymphoma cell lines and in primary tumor cells with the Fluorometric Microculture Cytotoxicity Assay and cell cycle analyses was performed in two of the cell lines. Melflufen was also investigated in a xenograft model with subcutaneous lymphoma cells inoculated in mice.

Results: Melflufen showed activity with cytotoxic IC50-values in the submicromolar range (0.011-0.92 μM) in the cell lines, corresponding to a mean of 49-fold superiority (p < 0.001) in potency vs. melphalan. In the primary cultures melflufen yielded slightly lower IC50-values (2.7 nM to 0.55 μM) and an increased ratio vs. melphalan (range 13–455, average 108, p < 0.001). Treated cell lines exhibited a clear accumulation in the G2/M-phase of the cell cycle. Melflufen also showed significant activity and no, or minimal side effects in the xenografted animals.

Conclusion: This study confirms previous reports of a targeting related potency superiority of melflufen compared to that of melphalan. Melflufen was active in cell lines and primary cultures of lymphoma cells, as well as in a xenograft model in mice and appears to be a candidate for further evaluation in the treatment of this group of malignant diseases.

Nyckelord
J1, Melflufen, Prodrug, Cancer therapeutics, Alkylating agents
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:uu:diva-282281 (URN)10.1186/s12885-016-2299-9 (DOI)000373330200001 ()27044263 (PubMedID)
Tillgänglig från: 2016-04-05 Skapad: 2016-04-05 Senast uppdaterad: 2017-11-30Bibliografiskt granskad
Carlier, C., Strese, S., Viktorsson, K., Velander, E., Nygren, P., Uustalu, M., . . . Gullbo, J. (2016). Preclinical activity of melflufen (J1) in ovarian cancer. OncoTarget, 7(37), 59322-59335
Öppna denna publikation i ny flik eller fönster >>Preclinical activity of melflufen (J1) in ovarian cancer
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2016 (Engelska)Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 37, s. 59322-59335Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Ovarian cancer carries a significant mortality. Since symptoms tend to be minimal, the disease is often diagnosed when peritoneal metastases are already present. The standard of care in advanced ovarian cancer consists of platinum-based chemotherapy combined with cytoreductive surgery. Unfortunately, even after optimal cytoreduction and adjuvant chemotherapy, most patients with stage III disease will develop a recurrence. Intraperitoneal administration of chemotherapy is an alternative treatment for patients with localized disease. The pharmacological and physiochemical properties of melflufen, a peptidase potentiated alkylator, raised the hypothesis that this drug could be useful in ovarian cancer and particularily against peritoneal carcinomatosis. In this study the preclinical effects of melflufen were investigated in different ovarian cancer models. Melflufen was active against ovarian cancer cell lines, primary cultures of patient-derived ovarian cancer cells, and inhibited the growth of subcutaneous A2780 ovarian cancer xenografts alone and when combined with gemcitabine or liposomal doxorubicin when administered intravenously. In addition, an intra-and subperitoneal xenograft model showed activity of intraperitoneal administered melflufen for peritoneal carcinomatosis, with minimal side effects and modest systemic exposure. In conclusion, results from this study support further investigations of melflufen for the treatment of peritoneal carcinomatosis from ovarian cancer, both for intravenous and intraperitoneal administration.

Nyckelord
ovarian cancer, melflufen, preclinical, in vivo, intraperitoneal treatment
Nationell ämneskategori
Cancer och onkologi Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:uu:diva-310031 (URN)10.18632/oncotarget.11163 (DOI)000387153900046 ()27528037 (PubMedID)
Tillgänglig från: 2016-12-12 Skapad: 2016-12-09 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
Eriksson, A., Gustafsson, M., Fryknäs, M., Gullbo, J., Nygren, P., Höglund, M. & Larsson, R. (2016). Repositioning Of Quinacrine For Treatment Of Acute Myeloid Leukemia - Synergies And In Vivo Effects. Paper presented at 21st Congress of the European-Hematology-Association, JUN 09-12, 2016, Copenhagen, DENMARK. Haematologica, 101, 367-368
Öppna denna publikation i ny flik eller fönster >>Repositioning Of Quinacrine For Treatment Of Acute Myeloid Leukemia - Synergies And In Vivo Effects
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2016 (Engelska)Ingår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, s. 367-368Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Nationell ämneskategori
Hematologi
Identifikatorer
urn:nbn:se:uu:diva-301452 (URN)000379484601269 ()
Konferens
21st Congress of the European-Hematology-Association, JUN 09-12, 2016, Copenhagen, DENMARK
Tillgänglig från: 2016-08-24 Skapad: 2016-08-23 Senast uppdaterad: 2017-11-28Bibliografiskt granskad
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