The understanding of the key role that androgens play on the normal and pathological physiology of the prostate guided the
development of different therapies for the treatment of locally advanced or ...metastatic prostate cancer (PCa). These so-called
androgen deprivation therapies include surgical or chemical castration, achieved by the administration of gonadotropin-releasing
hormone analogs; inhibition of steroidogenic enzymes; and finally, blocking of the binding of androgens to their receptor
(AR) by the use of antiandrogens. Despite an excellent initial response, in approximately 2 to 3 years, most of these patients
will succumb to the castration resistant form of the disease. Remarkably, even in the presence of castration levels of circulating
androgens, these tumors are still dependent on a functional AR, and several molecular mechanisms have been proposed to explain
this phenomenon. These include: (1) gene amplification and increased expression of the AR mRNA and protein, (2) selection
of mutations in the AR that confer broader ligand specificity, (3) changes in the ratios or expression between the AR and
its coregulators, (4) increased expression of steroidogenic enzymes, and (5) up-regulation of cross-talk signal transduction
pathways that can activate the AR in a ligand-independent manner. We will summarize how these molecular hypotheses are being
tested in the clinic by the latest therapeutic modalities.
Intra-tumor heterogeneity caused by clonal evolution is a major problem in cancer treatment. To address this problem, we performed label-free quantitative proteomics on primary acute myeloid leukemia ...(AML) samples. We identified 50 leukemia-enriched plasma membrane proteins enabling the prospective isolation of genetically distinct subclones from individual AML patients. Subclones differed in their regulatory phenotype, drug sensitivity, growth, and engraftment behavior, as determined by RNA sequencing, DNase I hypersensitive site mapping, transcription factor occupancy analysis, in vitro culture, and xenograft transplantation. Finally, we show that these markers can be used to identify and longitudinally track distinct leukemic clones in patients in routine diagnostics. Our study describes a strategy for a major improvement in stratifying cancer diagnosis and treatment.
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•Identification of clinically relevant leukemia-enriched plasma membrane proteins•Proteomics-informed prospective isolation of genetically distinct AML subclones•Subclones differ in transcription factor occupancy and transcriptional regulation•AML subclones display functional differences in vitro and in vivo
de Boer et al. identify plasma membrane proteins enriched on acute myeloid leukemia (AML) that enable prospective isolation of genetically distinct subclones with different functions from individual AML patients and can be used to longitudinally track distinct leukemic clones in patients in routine diagnostics.
BMS-754807 is a potent and reversible inhibitor of the insulin-like growth factor 1 receptor/insulin receptor family kinases
(Ki, <2 nmol/L). It is currently in phase I development for the treatment ...of a variety of human cancers. BMS-754807 effectively
inhibits the growth of a broad range of human tumor types in vitro , including mesenchymal (Ewing's, rhabdomyosarcoma, neuroblastoma, and liposarcoma), epithelial (breast, lung, pancreatic,
colon, gastric), and hematopoietic (multiple myeloma and leukemia) tumor cell lines (IC 50 , 5–365 nmol/L); the compound caused apoptosis in a human rhabdomyosarcoma cell line, Rh41, as shown by an accumulation of
the sub-G 1 fraction, as well as by an increase in poly ADP ribose polymerase and Caspase 3 cleavage. BMS-754807 is active in vivo in multiple (epithelial, mesenchymal, and hematopoietic) xenograft tumor models with tumor growth inhibition ranging from
53% to 115% and at a minimum effective dose of as low as 6.25 mg/kg dosed orally daily. Combination studies with BMS-754807
have been done on multiple human tumor cell types and showed in vitro synergies (combination index, <1.0) when combined with cytotoxic, hormonal, and targeted agents. The combination of cetuximab
and BMS-754807 in vivo , at multiple dose levels, resulted in improved clinical outcome over single agent treatment. These data show that BMS-754807
is an efficacious, orally active growth factor 1 receptor/insulin receptor family–targeted kinase inhibitor that may act in
combination with a wide array of established anticancer agents. Mol Cancer Ther 2009;8(12):3341–9
•JNJ-75276617 shows preclinical activity in KMT2A- or NPM1-altered leukemia, synergizing with gilteritinib, venetoclax, and azacitidine.•Antiproliferative activity in cells harboring menin mutations ...M327I and T349M is due to a unique binding mode.
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The interaction between menin and histone-lysine N-methyltransferase 2A (KMT2A) is a critical dependency for KMT2A- or nucleophosmin 1 (NPM1)–altered leukemias and an emerging opportunity for therapeutic development. JNJ-75276617 is a novel, orally bioavailable, potent, and selective protein-protein interaction inhibitor of the binding between menin and KMT2A. In KMT2A-rearranged (KMT2A-r) and NPM1-mutant (NPM1c) acute myeloid leukemia (AML) cells, JNJ-75276617 inhibited the association of the menin-KMT2A complex with chromatin at target gene promoters, resulting in reduced expression of several menin-KMT2A target genes, including MEIS1 and FLT3. JNJ-75276617 displayed potent antiproliferative activity across several AML and acute lymphoblastic leukemia (ALL) cell lines and patient samples harboring KMT2A or NPM1 alterations in vitro. In xenograft models of AML and ALL, JNJ-75276617 reduced leukemic burden and provided a significant dose-dependent survival benefit accompanied by expression changes of menin-KMT2A target genes. JNJ-75276617 demonstrated synergistic effects with gilteritinib in vitro in AML cells harboring KMT2A-r. JNJ-75276617 further exhibited synergistic effects with venetoclax and azacitidine in AML cells bearing KMT2A-r in vitro, and significantly increased survival in mice. Interestingly, JNJ-75276617 showed potent antiproliferative activity in cell lines engineered with recently discovered mutations (MEN1M327I or MEN1T349M) that developed in patients refractory to the menin-KMT2A inhibitor revumenib. A cocrystal structure of menin in complex with JNJ-75276617 indicates a unique binding mode distinct from other menin-KMT2A inhibitors, including revumenib. JNJ-75276617 is being clinically investigated for acute leukemias harboring KMT2A or NPM1 alterations, as a monotherapy for relapsed/refractory acute leukemia (NCT04811560), or in combination with AML-directed therapies (NCT05453903).
We have reported previously the activity of the insulin-like growth factor-I (IGF-IR)/insulin receptor (InsR) inhibitor, BMS-554417,
in breast and ovarian cancer cell lines. Further studies indicated ...treatment of OV202 ovarian cancer cells with BMS-554417
increased phosphorylation of HER-2. In addition, treatment with the pan-HER inhibitor, BMS-599626, resulted in increased phosphorylation
of IGF-IR, suggesting a reciprocal cross-talk mechanism. In a panel of five ovarian cancer cell lines, simultaneous treatment
with the IGF-IR/InsR inhibitor, BMS-536924 and BMS-599626, resulted in a synergistic antiproliferative effect. Furthermore,
combination therapy decreased AKT and extracellular signal-regulated kinase activation and increased biochemical and nuclear
morphologic changes consistent with apoptosis compared with either agent alone. In response to treatment with BMS-536924,
increased expression and activation of various members of the HER family of receptors were seen in all five ovarian cancer
cell lines, suggesting that inhibition of IGF-IR/InsR results in adaptive up-regulation of the HER pathway. Using MCF-7 breast
cancer cell variants that overexpressed HER-1 or HER-2, we then tested the hypothesis that HER receptor expression is sufficient
to confer resistance to IGF-IR-targeted therapy. In the presence of activating ligands epidermal growth factor or heregulin,
respectively, MCF-7 cells expressing HER-1 or HER-2 were resistant to BMS-536924 as determined in a proliferation and clonogenic
assay. These data suggested that simultaneous treatment with inhibitors of the IGF-I and HER family of receptors may be an
effective strategy for clinical investigations of IGF-IR inhibitors in breast and ovarian cancer and that targeting HER-1
and HER-2 may overcome clinical resistance to IGF-IR inhibitors. Mol Cancer Ther 2008;7(9):2589–98
T cell redirection mediated by bispecific antibodies (BsAbs) is a promising cancer therapy. Dual antigen binding is necessary for potent T cell redirection and is influenced by the structural ...characteristics of a BsAb, which are dependent on its IgG subclass. In this study, model BsAbs targeting CD19xCD3 were generated in variants of IgG1, IgG2, and IgG4 carrying Fc mutations that reduce FcγR interaction, and two chimeric IgG subclasses termed IgG1:2 and IgG4:2, in which the IgG1- or IgG4-F(ab)
are grafted on an IgG2 Fc. Molecules containing an IgG2 or IgG4-F(ab)
domain were confirmed to be the most structurally compact molecules. All BsAbs were shown to bind both of their target proteins (and corresponding cells) equally well. However, CD19xCD3 IgG2 did not bind both antigens simultaneously as measured by the absence of cellular clustering of T cells with target cells. This translated to a reduced potency of IgG2 BsAbs in T-cell redirection assays. The activity of IgG2 BsAbs was fully restored in the chimeric subclasses IgG4:2 and IgG1:2. This confirmed the major contribution of the F(ab)
region to the BsAb's functional activity and demonstrated that function of BsAbs can be modulated by engineering molecules combining different Fc and F(ab)
domains.
ADCC: Antibody-dependent cellular cytotoxicity; AlphaScreen
: Amplified Luminescent Proximity Homogeneous Assay Screening; ANOVA: Analysis of variance; BiTE: bispecific T-cell engager; BSA: bovine serum albumin; BsAb: bispecific antibody; cFAE: controlled Fab-arm exchange; CDC: complement-dependent cellular cytotoxicity; CIEX: cation-exchange; CIR: chimeric immune receptor; DPBS: Dulbecco's phosphate-buffered saline; EC
value: effective concentration to reach half-maximum effect; EGFR: epidermal growth factor receptor; EI: expansion index (RA
/RA
); FACS: fluorescence-activated cell sorting; FVD: fixable viability dye; HI-HPLC: hydrophobic interaction HPLC; HI-FBS: heat-inactivated fetal bovine serum; HPLC: high-pressure liquid chromatography; IC
value: effective concentration to reach half-maximum inhibition; IQ: Inhibition Quotient; IS: immunological synapse; MES: 2-(N-morpholino)ethanesulfonic acid; R-PE: recombinant phycoerythrin; RA: red area in μm
/well; RD: receptor density; RFP: red fluorescent protein; R
: radius of gyration; RSV: respiratory syncytial virus; SAXS: small-angle x-ray scattering; scFv: single-chain variable fragment; SD: standard deviation; SPR: surface plasmon resonance; WT: wild-type.
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Dihydroorotate dehydrogenase (DHODH) enzymatic activity impacts many aspects critical to cell proliferation and survival. Recently, DHODH has been identified as a target for acute ...myeloid differentiation therapy. In preclinical models of AML, the DHODH inhibitor Brequinar (BRQ) demonstrated potent anti-leukemic activity. Herein we describe a carboxylic acid isostere study of Brequinar which revealed a more potent non-carboxylic acid derivative with improved cellular potency and good pharmacokinetic properties.
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