Concomitant Delivery of Pirarubicin and Salinomycin Synergistically Enhanced the Efficacy of Cancer Therapy and Reduced the Risk of Cancer Relapse.

Pirarubicin attracted considerable attention in clinical studies because of its high therapeutic efficacy and reduced toxicity in comparison with other anthracyclines. Nevertheless, ~ 30% patients undergoing PIRA treatment still experience relapse and metastasis. Clinical advancements unveiled that cancer stem cells (CSCs) residing in the tumor constitutes a major factor for such limitations and subsequently are the reason for treatment failure. Consequently, eradicating CSCs alongside bulk tumor is a crucial undertaking to attain utmost therapeutic efficacy of the treatment. Nevertheless, majority of the CSCs inhibitors currently under examination lack specificity, show unsynchronized bioavailability with other primary treatments and exhibit notable toxicity in their therapeutic applications, which is primarily attributable to their inadequate tumor-targeting capabilities. Therefore, we have developed a biodegradable polylactic acid based blend block copolymeric NPs for concomitant delivery of CSCs inhibitor Salinomycin (SAL) & chemotherapeutic drug Pirarubicin (PIRA) with an aim to improve the efficacy of treatment and prevent cancer relapse. Prepared NPs showed < 100 nm size and excellent loading with sustained release for both the drugs. Also, PIRA:SAL co-loaded NPs exhibits synergistically enhanced cytotoxicity against cancer cell as well as CSCs. Most importantly, NPs mediated co-delivery of the drugs showed complete tumor eradication, without any reoccurrence throughout the surveillance period. Additionally, NPs treatment didn't show any histopathological alteration in vital organs confirming their non-toxic nature. Altogether, present study concludes that the developed PIRA:SAL NPs have excellent efficacy for tumor regression as well as prevention of cancer relapse, hence can be used as a potential combination therapy for cancer treatment.

Polylactic acid based polymeric nanoparticle mediated co-delivery of navitoclax and decitabine for cancer therapy.

Combination chemotherapy with systemic administration of drugs in their free form can be challenging due to non-synchronized pharmacokinetics and sub-optimal tumor accumulation. The present study investigates a PLA-based block copolymeric nanocarrier for the co-delivery of navitoclax and decitabine (NAV/DCB NPs) for combination cancer therapy. NAV/DCB NPs exhibited potent in vitro synergistic cytotoxicity in both acute myeloid leukemia and breast cancer cell lines. Biodistribution studies of NAV/DCB NPs in tumor bearing mice, showed significant drug accumulation in tumor tissue and detectable quantities in plasma even after 48 h. Good hemocompatibility with reduced in vivo platelet toxicity indicated that encapsulation in PLA-based nanocarrier helped ameliorate navitoclax associated thrombocytopenia. In vivo biological activity of NAV/DCB NPs evaluated in xenograft AML and syngeneic breast cancer model, demonstrated potent tumor growth inhibition efficacy. PLA-based NAV/DCB dual NPs present a novel, safe and effective nanoformulation for combination cancer therapy in both solid tumors and hematologic malignancies.

Concomitant Delivery of Paclitaxel and NuBCP-9 peptide for synergistic enhancement of cancer therapy.

Paclitaxel (PTX) is a microtubule inhibitor administered as an albumin-bound nanoformulation for the treatment of breast cancer. However, the effectiveness of PTX is limited by resistance mechanisms mediated in part by upregulation of the anti-apoptotic BCL-2 and P-glycoprotein (P-gp). Present investigation was designed to study the synergistic potential of NuBCP-9 and PTX loaded polymeric nanoparticles to minimize the dose and improve the efficacy and safety. PTX and NuBCP-9 loaded polylactic acid-polyethylene glycol-polypropylene glycol-polyethylene glycol [PLA-(PEG-PPG-PEG)] nanoparticles were prepared by double emulsion solvent evaporation method. PTX and NuBCP-9 loaded NPs displayed an average size of 90 nm with spherical morphology. PTX and NuBCP-9 dual loaded NPs reducedIC50 by ~40-fold and acted synergistically. Treatment of the syngeneic EAT mice with PTX-NuBCP-9/NPs resulted in improved efficacy than that alone treated mice. Overall, the concomitant delivery PTX and NuBCP-9 loaded NPs showed superior activity than that of PTX and NuBCP-9 alone treated mice.

Targeting MUC1-C inhibits the AKT-S6K1-elF4A pathway regulating TIGAR translation in colorectal cancer.

BACKGROUND: Colorectal cancer is third most common malignancy and is the second most common cause of cancer-related death. The MUC1 heterodimeric protein is aberrantly overexpressed in colorectal cancer and has been linked to poor outcomes in this disease. Here, we investigate the effects of the MUC1-C subunit inhibitor (GO-203), which disrupts MUC1-C homo-oligomerization, on human colorectal cancer cells. METHODS: TIGAR mRNA level was determined using qRT-PCR. Western blotting was used to measure TIGAR protein level and AKT-mTOR-S6K1 pathways. Reactive oxygen species and apoptosis were measured by flow cytometry. Effect of MUC1-C peptide, GO-203 was studied on colorectal xenograft tumors. Immunohistochemistry was utilized for TIGAR staining. RESULTS: Treatment of MUC1-overexpressing SKCO-1 and Colo-205 colon cancer cells with GO-203 was associated with downregulation of the TP53-inducible glycolysis and apoptosis regulator (TIGAR) protein. TIGAR promotes the shunting of glycolytic intermediates into the pentose phosphate pathway and thus is of importance for maintaining redox balance. We show that GO-203-induced suppression of TIGAR is mediated by inhibition of AKT and the downstream mTOR pathway. The results also demonstrate that targeting MUC1-C blocks eIF4A cap-dependent translation of TIGAR. In concert with these results, GO-203-induced suppression of TIGAR was associated with decreases in GSH levels. GO-203 treatment also resulted in increases in reactive oxygen species (ROS) and loss of mitochondrial transmembrane potential. Consistent with these results, GO-203 inhibited the growth of colon cancer cells in vitro and as xenografts in nude mice. Inhibition of MUC1-C also downregulated TIGAR expression in xenograft tissues. CONCLUSIONS: These findings indicate that MUC1-C is a potential target for the treatment of colorectal cancer. Colorectal cancer patients who overexpress MUC1-C may be candidates for treatment with the MUC1-C inhibitor alone or in combination therapy with other agents.

Systemic delivery of the tumor necrosis factor gene to tumors by a novel dual DNA-nanocomplex in a nanoparticle system.

Many cancers fail to respond to immunotherapy as a result of immune suppression by the tumor microenvironment. The exogenous expression of immune cytokines to reprogram the tumor microenvironment represents an approach to circumvent this suppression. The present studies describe the development of a novel dual nanoparticle (DNP) system for driving DNA expression vectors encoding inflammatory cytokines in tumor cells. The DNP system consists of a DNA expression vector-cationic peptide nanocomplex (NC) surrounded by a diblock polymeric NP. Tumor necrosis factor alpha (TNF) was selected as the prototype cytokine for this system, based on its pleotropic inflammatory and anti-cancer activities. Our results demonstrate that the DNP system is highly effective in driving expression of TNF in tumor cells. We also demonstrate that the DNPs are effective in inducing apoptosis and anti-tumor activity. These findings support a novel immunotherapeutic approach for the intratumoral delivery of DNA vectors that express inflammatory cytokines.

MUC1-C oncoprotein promotes FLT3 receptor activation in acute myeloid leukemia cells.

Blasts from approximately one-third of patients with acute myeloid leukemia (AML) harbor activating mutations in the FMS-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase that confer a poor prognosis. The Mucin 1-C-terminal subunit (MUC1-C) oncoprotein is aberrantly expressed in AML blasts and stem cells; however, there is no known interaction between MUC1-C and FLT3. The present studies demonstrate that MUC1-C associates with wild-type and mutant FLT3 in AML cells. Targeting MUC1-C with the cell-penetrating peptide inhibitor GO-203 disrupts MUC1-C/FLT3 complexes and downregulates FLT3 activation. GO-203 treatment of AML cells was also associated with inhibition of the FLT3 downstream effectors AKT, extracellular signal-regulated kinase, and STAT5. The results further show that AML cells with FLT3-activating mutations and resistant to the FLT3 inhibitor midostaurin/PKC412 are sensitive to GO-203-induced growth arrest and death. Moreover, GO-203 increases sensitivity of mutant FLT3 AML cells to FLT3 inhibitor treatment. These results indicate that MUC1-C contributes to FLT3 activation in AML cells and that targeting MUC1-C inhibits the FLT3 signaling pathway. Our findings support the development of MUC1-C inhibitors alone and in combination with agents that target FLT3 for the treatment of wild-type and mutant FLT3 AML.

MUC1 oncoprotein activates the IkappaB kinase beta complex and constitutive NF-kappaB signalling.

Nuclear factor-kappaB (NF-kappaB) is constitutively activated in diverse human malignancies by mechanisms that are not understood. The MUC1 oncoprotein is aberrantly overexpressed by most human carcinomas and, similarly to NF-kappaB, blocks apoptosis and induces transformation. This study demonstrates that overexpression of MUC1 in human carcinoma cells is associated with constitutive activation of NF-kappaB p65. We show that MUC1 interacts with the high-molecular-weight IkappaB kinase (IKK) complex in vivo and that the MUC1 cytoplasmic domain binds directly to IKKbeta and IKKgamma. Interaction of MUC1 with both IKKbeta and IKKgamma is necessary for IKKbeta activation, resulting in phosphorylation and degradation of IkappaBalpha. Studies in non-malignant epithelial cells show that MUC1 is recruited to the TNF-R1 complex and interacts with IKKbeta-IKKgamma in response to TNFalpha stimulation. TNFalpha-induced recruitment of MUC1 is dependent on TRADD and TRAF2, but not the death-domain kinase RIP1. In addition, MUC1-mediated activation of IKKbeta is dependent on TAK1 and TAB2. These findings indicate that MUC1 is important for physiological activation of IKKbeta and that overexpression of MUC1, as found in human cancers, confers sustained induction of the IKKbeta-NF-kappaB p65 pathway.

MUC1-C oncoprotein suppresses reactive oxygen species-induced terminal differentiation of acute myelogenous leukemia cells.

Acute myeloid leukemia (AML) cells are characterized by unlimited self-renewal and an impaired capacity to undergo terminal differentiation. The MUC1 oncoprotein is aberrantly expressed in AML cells; however, there has been no evidence for involvement of MUC1 in myeloid leukemogenesis. Cell-penetrating peptide inhibitors of the MUC1-C subunit block its oligomerization and thereby oncogenic function. The present results demonstrate that treatment of human MOLM-14 and MV4-11 AML cells with these inhibitors is associated with arrest of growth, induction of late apoptosis/necrosis, and loss of self-renewal capacity. Similar results were obtained with primary blasts from patients with AML. Inhibition of MUC1-C was associated with increases in reactive oxygen species (ROS) and depletion of glutathione. Increases in ROS have been linked to induction of hematopoietic cell differentiation along the myeloid lineage. In this regard, inhibition of MUC1-C was associated with induction of a terminally differentiated myeloid phenotype in AML cell lines and primary blasts by an ROS-dependent mechanism. These findings indicate that MUC1-C function is of importance to AML cell self-renewal and that inhibition of MUC1-C represents a potential therapeutic approach to induce terminal differentiation of AML cells.

Polylactic acid based biodegradable hybrid block copolymeric nanoparticle mediated co-delivery of salinomycin and doxorubicin for cancer therapy.

Existence of cancer stem cells (CSCs) are primarily responsible for chemoresistance, cancer reoccurrence and treatment failure in cancer patients. Eliminating CSCs along with bulk tumor is a necessity to achieve complete cancer inhibition. Salinomycin (SAL) has potential to specifically target and kill CSCs through blocking their multiple pathways simultaneously. SAL has also been reported to improve anti-cancer efficacy of numerous chemo-based drugs when used in combination therapy. However, clinical use of SAL is restricted due to its high off targeted toxicity. Herein, we have developed a PLA based hybrid block copolymer for concomitant delivery of SAL and doxorubicin (DOX) with an aim to reduce their adverse side effects and enhance the therapeutic efficacy of the treatment. Designed PLA based nanoplatform showed high encapsulation and sustained release profile for both the drugs. Cytotoxicity evaluation on cancer cell lines confirmed the synergistic effect of SAL:DOX co-loaded NPs. Additionally, prepared SAL NPs were also found to be highly effective against chemo-resistant cancer cells and CSCs derived from cancer patient. Most importantly, encapsulation of SAL in PLA NPs improved its pharmacokinetics and biodistribution profile. Consequently, undesired toxicity with SAL NPs was significantly reduced which in-turn increased the dose tolerability in mice as compared to free SAL. Treatment of EAC tumor bearing mice with SAL:DOX co-loaded NPs resulted in excellent tumor regression and complete inhibition of cancer reoccurrence. These results conclude that concomitant delivery of SAL and DOX using PLA based block copolymeric nano-carrier have a strong potential for cancer therapy.

Quatramer™ encapsulation of dual-targeted PI3-Kδ/HDAC6 inhibitor, HSB-510, suppresses growth of breast cancer.

Multiple studies have shown that the progression of breast cancer depends on multiple signaling pathways, suggesting that therapies with multitargeted anticancer agents will offer improved therapeutic benefits through synergistic effects in inhibiting cancer growth. Dual-targeted inhibitors of phosphoinositide 3-kinase (PI3-K) and histone deacetylase (HDAC) have emerged as promising cancer therapy candidates. However, poor aqueous solubility and bioavailability limited their efficacy in cancer. The present study investigates the encapsulation of a PI3-Kδ/HDAC6 dual inhibitor into hybrid block copolymers (polylactic acid-methoxy polyethylene glycol; polylactic acid-polyethylene glycol-polypropylene glycol-polyethylene glycol-polylactic acid) (HSB-510) as a delivery system to target PI3-Kδ and HDAC6 pathways in breast cancer cells. The prepared HSB-510 showed an average diameter of 96 ± 3 nm, a zeta potential of -17 ± 2 mV, and PDI of ˂0.1 with a slow and sustained release profile of PI3-Kδ/HDAC6 inhibitors in a nonphysiological buffer. In vitro studies with HSB-510 have demonstrated substantial growth inhibition of breast cancer cell lines, MDA-MB-468, SUM-149, MCF-7, and Ehrlich ascites carcinoma (EAC) as well as downregulation of phospho-AKT, phospho-ERK, and c-Myc levels. Importantly, bi-weekly treatment of Balb/c wild-type mice harboring EAC cells with HSB-510 at a dose of 25 mg/kg resulted in significant tumor growth inhibition. The treatment with HSB-510 was without any significant effect on the body weights of the mice. These results demonstrate that a novel Quatramer encapsulation of a PI3-Kδ/HDAC6 dual inhibitor (HSB-510) represents an approach for the successful targeting of breast cancer and potentially other cancer types.

MUC1-C oncoprotein confers androgen-independent growth of human prostate cancer cells.

BACKGROUND: The mucin 1 (MUC1) heterodimeric oncoprotein is overexpressed in human prostate cancers with aggressive pathologic and clinical features. However, few insights are available regarding the functional role of MUC1 in prostate cancer. METHODS: Effects of MUC1-C on androgen receptor (AR) expression were determined by RT-PCR, immunoblotting and AR promoter activation. Coimmunoprecipitations, direct binding assays, and chromatin immunoprecipitation (ChIP) studies were performed to assess the interaction between MUC1-C and AR. Cells were analyzed for invasion, growth in androgen-depleted medium, and sensitivity to MUC1-C inhibitors. RESULTS: The present studies in androgen-dependent LNCaP and LAPC4 prostate cancer cells demonstrate that the oncogenic MUC1-C subunit suppresses AR expression. The results show that MUC1-C activates a posttranscriptional mechanism involving miR-135b-mediated downregulation of AR mRNA levels. The results further demonstrate that MUC1-C forms a complex with AR through a direct interaction between the MUC1-C cytoplasmic domain and the AR DNA-binding domain (DBD). In addition, MUC1-C associates with AR in a complex that occupies the PSA promoter. The interaction between MUC1-C and AR is associated with induction of the epithelial-mesenchymal transition (EMT) and increased invasion. MUC1-C also conferred growth in androgen-depleted medium and resistance to bicalutamide treatment. Moreover, expression of MUC1-C resulted in sensitivity to the MUC1-C inhibitor GO-203 with inhibition of growth in vitro. GO-203 treatment also inhibited growth of established tumor xenografts in nude mice. CONCLUSIONS: These findings indicate that MUC1-C suppresses AR expression in prostate cancer cells and confers a more aggressive androgen-independent phenotype that is sensitive to MUC1-C inhibition.

Human MUC1 carcinoma-associated protein confers resistance to genotoxic anticancer agents.

The MUC1 transforming protein is overexpressed by most human carcinomas. The present studies demonstrate that the MUC1 C-terminal subunit (MUC1 C-ter) localizes to mitochondria in HCT116/MUC1 colon carcinoma cells and that heregulin stimulates mitochondrial targeting of MUC1 C-ter. We also show that MUC1 attenuates cisplatin-induced (1) release of mitochondrial apoptogenic factors, (2) activation of caspase-3, and (3) induction of apoptosis. Moreover, knockdown of MUC1 expression in A549 lung and ZR-75-1 breast carcinoma cells by MUC1siRNA was associated with increased sensitivity to genotoxic drugs in vitro and in vivo. These findings indicate that MUC1 attenuates the apoptotic response to DNA damage and that this oncoprotein confers resistance to genotoxic anticancer agents.

Quatramer™ mediated co-delivery of PI3-Kδ/HDAC6 dual inhibitor augments the anti-cancer efficacy of Epirubicin in breast cancer.

The disruption and overexpression of phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway in cancer results in tumor growth, metastasis, and survival. Treatment with common anthracyclines has confirmed cancer cells' dependence on PI3K pathway through overexpression of AKT. Moreover, combining HDAC inhibitor with anthracycline has shown the targeting of breast cancer stem cells. Therefore, it has been hypothesized that the co-delivery of PI3-Kδ/HDAC6 dual inhibitor with Epirubicin using polymeric nanoparticle could increase the anti-cancer treatment efficacy with reduced toxicity. Pluronic modified polylactic acid block copolymer (quatramer) was used for co-encapsulation of PI3-Kδ/HDAC6 and Epirubicin. The co-encapsulated nanoparticles, PI3-Kδ/HDAC6-Epi-NPs have shown size of 99 ± 3 nm, PDI of 0.18 ± 0.07 with a sustained and slow-release profile in non-physiological buffer (PBS, pH 7.4). The in-vitro cell proliferation inhibition studies done on 2D and 3D culture of breast cancer cell lines have confirmed the synergistic effect of PI3-Kδ/HDAC6-Epi-NPs with lower IC50 values compared to PI3-Kδ/HDAC6-NPs and Epi-NPs. Additionally, intravenous twice a week treatment for three weeks with PI3-Kδ/HDAC6-Epi-NPs resulted in complete tumor eradication in the syngeneic breast tumor mice model. In comparison, the PI3-Kδ/HDAC6-NPs and Epi-NPs resulted in tumor growth inhibition of 15.86% and 81.59%, respectively. These studies predicted that clinical use of PI3-Kδ/HDAC6-Epi-NPs will be effective in breast cancer treatments.

Development and evaluation of PLA based hybrid block copolymeric nanoparticles for systemic delivery of pirarubicin as an anti-cancer agent.

Pirarubicin (PIRA) is a semi-synthetic anthracycline derivative that is reported to have lesser toxicity and better clinical outcomes as compared to its parental form doxorubicin (DOX). However, long term use of PIRA causes bone marrow suppression and severe cardiotoxicity to the recipients. Herein, we have developed a biodegradable polymeric nano platform consisting of amphiphilic di-block copolymer methoxy polyethylene glycol-polylactic acid and a hydrophobic penta-block copolymer polylactic acid-pluronic L-61-polylactic acid as a hybrid system to prepare PIRA (& DOX) encapsulated nanoparticles (NPs) with an aim to reduce its off targeted toxicity and enhance therapeutic efficacy for cancer therapy. Prepared PIRA/DOX NPs showed uniform particle size distribution, high encapsulation efficiency and sustained drug release profile. Cytotoxicity evaluation of PIRA NPs against TNBC cells and mammospheres showed its superior anti-cancer activity over DOX NPs. Anti-cancer efficacy of PIRA/DOX NPs was found significantly enhanced in presence of penta-block copolymer which confirmed chemo-sensitising ability of pluronic L-61. Most importantly, encapsulation of PIRA/DOX in the NPs reduced their off targeted toxicity and increased the maximum tolerated dose in BALB/c mice. Moreover, treatment of EAC tumor harbouring mice with PIRA NPs resulted in higher tumor regression as compared with the groups treated with free PIRA, free DOX or DOX NPs. Altogether, the results conclude that prepared PIRA NPs exhibits an excellent anti-cancer therapeutic efficacy and has a strong potential for cancer therapy.

Co-encapsulation of PI3-Kδ/HDAC6 dual inhibitor and Navitoclax in Quatramer™ nanoparticles for synergistic effect in ER+ breast cancer.

Progression and metastasis of ER+ breast cancer depend on multiple signaling cascades. The available conventional treatment options have limited efficacy in ER+ breast cancer due to overexpression of AKT, c-Myc and BCL-2 proteins. Simultaneous targeting and inhibition of these targets in ER+ cancer may result in effective therapeutic outcomes. However, combining two or more free drug molecules to treat cancer leads to unsynchronised pharmacokinetics, toxicity, and eventual resistance development. To overcome these limitations, a novel nanoformulation of PI3-Kδ/HDAC6 dual inhibitor in combination with Navitoclax is developed using Pluronic modified PLA based hybrid block copolymer. The prepared dual drug loaded PI3-Kδ/HDAC6-NAV-NPs (1:3-NPs) have shown high encapsulation efficiency, hydrodynamic size, and polydispersity of âˆ¼ 93 %, 159 ± 2.6 nm, and 0.19 ± 0.03, respectively. These PI3-Kδ/HDAC6-NAV-NPs exhibit slow and sustained release profiles of PI3-Kδ/HDAC6 inhibitor and NAV in phosphate buffer saline (PBS, pH 7.4). The in-vitro cytotoxicity studies done with PI3-Kδ/HDAC6-NAV-NPs in ER+ breast cancer cell lines have shown a synergistic effect with lower IC50 values compared to individual NAV-NPs and PI3-Kδ/HDAC6-NPs. The PI3-Kδ/HDAC6-NAV-NPs treatment (4 mg/kg, I.V., twice a week for three weeks) of ER+ breast cancer syngeneic mice tumor model resulted in complete tumor eradication without any overt toxicity. These results demonstrate that a unique formulation of a novel PI3-Kδ/HDAC6 dual inhibitor in combination with Navitoclax represents an approach for an efficient treatment option for ER+ breast cancer.

Survival of human multiple myeloma cells is dependent on MUC1 C-terminal transmembrane subunit oncoprotein function.

The MUC1 C-terminal transmembrane subunit (MUC1-C) oncoprotein is a direct activator of the canonical nuclear factor-kappaB (NF-kappaB) RelA/p65 pathway and is aberrantly expressed in human multiple myeloma cells. However, it is not known whether multiple myeloma cells are sensitive to the disruption of MUC1-C function for survival. The present studies demonstrate that peptide inhibitors of MUC1-C oligomerization block growth of human multiple myeloma cells in vitro. Inhibition of MUC1-C function also blocked the interaction between MUC1-C and NF-kappaB p65 and activation of the NF-kappaB pathway. In addition, inhibition of MUC1-C in multiple myeloma cells was associated with activation of the intrinsic apoptotic pathway and induction of late apoptosis/necrosis. Primary multiple myeloma cells, but not normal B-cells, were also sensitive to MUC1-C inhibition. Significantly, treatment of established U266 multiple myeloma xenografts growing in nude mice with a lead candidate MUC1-C inhibitor resulted in complete tumor regression and lack of recurrence. These findings indicate that multiple myeloma cells are dependent on intact MUC1-C function for constitutive activation of the canonical NF-kappaB pathway and for their growth and survival.

Peptide-based combination nanoformulations for cancer therapy.

Research in cancer therapy is moving towards the use of biomolecules in combination with conventional approaches for improved disease outcome. Among the biomolecules explored, peptides are strong contenders due to their small size, high specificity, low systemic toxicity and wide inter/intracellular targets. The use of nanoformulations for such combination approaches can lead to further improvement in efficacy by reducing off-target cytotoxicity, increasing circulation time, tumor penetration and accumulation. This review focuses on nanodelivery systems for peptide-based combinations with chemo, immuno, radiation and hormone therapy. It gives an overview of the latest therapeutic research being conducted using combination nanoformulations with anticancer peptides, cell penetrating/tumor targeting peptides, peptide nanocarriers, peptidomimetics, peptide-based hormones and peptide vaccines. The challenges hindering clinical translation are also discussed.

Design, Synthesis, and Biological Evaluation of Quinazolin-4-one-Based Hydroxamic Acids as Dual PI3K/HDAC Inhibitors.

A series of quinazolin-4-one based hydroxamic acids was rationally designed and synthesized as novel dual PI3K/HDAC inhibitors by incorporating an HDAC pharmacophore into a PI3K inhibitor (Idelalisib) via an optimized linker. Several of these dual inhibitors were highly potent (IC50 < 10 nM) and selective against PI3Kγ, δ and HDAC6 enzymes and exhibited good antiproliferative activity against multiple cancer cell lines. The lead compound 48c, induced necrosis in several mutant and FLT3-resistant AML cell lines and primary blasts from AML patients, while showing no cytotoxicity against normal PBMCs, NIH3T3, and HEK293 cells. Target engagement of PI3Kδ and HDAC6 by 48c was demonstrated in MV411 cells using the cellular thermal shift assay (CETSA). Compound 48c showed good pharmacokinetics properties in mice via intraperitoneal (ip) administration and provides a means to examine the biological effects of inhibiting these two important enzymes with a single molecule, either in vitro or in vivo.

MUC1-C drives stemness in progression of colitis to colorectal cancer.

Colitis is associated with the development of colorectal cancer (CRC) by largely undefined mechanisms that are critical for understanding the link between inflammation and cancer. Intestinal stem cells (ISCs) marked by leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) expression are of importance in both the inflammatory response to colitis and progression to colitis-associated colon cancer (CACC). Here, we report in human mucin 1-transgenic (MUC1-transgenic) mouse models of CACC, targeting the MUC1-C oncogenic protein suppresses the (a) Lgr5+ ISC population, (b) induction of Myc and core pluripotency stem cell factors, and (c) severity and progression of colitis to dysplasia and cancer. By extension to human colon cancer cells, we demonstrate that MUC1-C drives MYC, forms a complex with MYC on the LGR5 promoter, and activates LGR5 expression. We also show in CRC cells that MUC1-C induces cancer stem cell (CSC) markers (BMI1, ALDH1, FOXA1, LIN28B) and the OCT4, SOX2, and NANOG pluripotency factors. Consistent with conferring the CSC state, targeting MUC1-C suppresses the capacity of CRC cells to promote wound healing, invasion, self-renewal, and tumorigenicity. In analysis of human tissues, MUC1 expression associates with activation of inflammatory pathways, development of colitis, and aggressiveness of CRCs. These results collectively indicate that MUC1-C is of importance for integrating stemness and pluripotency in colitis and CRC. Of clinical relevance, the findings further indicate that MUC1-C represents a potentially previously unrecognized target that is druggable for treating progression of colitis and CRC.