Differentiation Therapy Of Cancer Research Articles

Structural modification of 2-phenylquinoline-4-carboxylic acid containing SIRT3 inhibitors for the cancer differentiation therapy.

Inhibition of SIRT3 exhibited potency in triggering leukemic cell differentiation. In discovery of potent SIRT3 inhibitors for cancer differentiation therapy, structural modification was performed on the previously developed lead compound P6. A total of 33 compounds were designed and synthesized. In the enzyme inhibitory assay, several molecules S18, S26, S27 and T5 showed potent SIRT3 inhibitory activity with IC50 value of 0.53, 1.86, 5.06, and 2.88 μM, respectively. Moreover, the tested compounds exhibited SIRT3 inhibitory selectivity over SIRT1 and SIRT2. Compounds S27 and T5 were potent in inhibition the growth of MM1.S and RPMI-8226 cells in the invitro antiproliferative test. Significantly, representative compounds, especially S27 and T5, promoted differentiation of tested MM cells in the cellular morphological evaluation, accompanied by increasing the expression of differentiation antigen CD49e and human immunoglobulin light chain lambda and kappa. Additionally, molecule S18 without antiproliferative potency itself, showed significant inhibitory activity against growth factor IL-6 induced RPMI-8226 cell proliferation. Collectively, potent SIRT3 selective inhibitors with MM cell differentiation potency were developed for further discovery of anticancer drugs.

Nonlinear control designs and their application to cancer differentiation therapy

We designed three new controllers: a sigmoid-based controller, a polynomial dynamic inversion-based controller, and a proportional–integral–derivative (PID) impulsive controller for cancer differentiation therapy. We compared these three controllers to existing control strategies to show the improvement in performance and compare their robustness. The sigmoid-based controller adds a sigmoid term associated with the error of the controlled state and a selected observed state. The sigmoid term is multiplied by a control gain, thereby decreasing the control effort for state transition. The polynomial dynamic inversion-based controller adds a cubic error term in the error dynamic aiming to achieve a shorter convergence time to the desired value of the controlled state. The PID impulsive controller considers the accumulated controlled state error and the rate of change of the controlled state error, thereby forcing the controlled state to converge to the desired value and alleviating the damping effect in the steady state. For the considered cancer network, the 3 new cancer control strategies exhibit superior and robust performance. The PID impulsive controller has a significant improvement in robustness compared to the impulsive controller and has greater potential for cancer differentiation therapy.

Cell Reprogramming Techniques: Contributions to Cancer Therapy.

The reprogramming of terminally differentiated cells over the past few years has become important for induced pluripotent stem cells (iPSCs) in the field of regenerative medicine and disease drug modeling. At the same time, iPSCs have also played an important role in human cancer research. iPSCs derived from cancer patients can be used to simulate the early progression of cancer, for drug testing, and to study the molecular mechanism of cancer occurrence. In recent years, with the application of cellular immunotherapy in cancer therapy, patient-derived iPSC-induced immune cells (T, natural killer, and macrophage cells) solve the problem of immune rejection and have higher immunogenicity, which greatly improves the therapeutic efficiency of immune cell therapy. With the continuous progress of cancer differentiation therapy, iPSC technology can reprogram cancer cells to a more primitive pluripotent undifferentiated state, and successfully reverse cancer cells to a benign phenotype by changing the epigenetic inheritance of cancer cells. This article reviews the recent progress of cell reprogramming technology in human cancer research, focuses on the application of reprogramming technology in cancer immunotherapy and the problems solved, and summarizes the malignant phenotype changes of cancer cells in the process of reprogramming and subsequent differentiation.

HES1 deficiency impairs development of human intestinal mesenchyme by suppressing WNT5A expression

Serious intestinal side-effects that target the NOTCH-HES1 pathway in human cancer differentiation therapy make it necessary to understand the pathway at the human organ level. Herein, we endogenously introduced HES1−/− mutations into human embryonic stem cells (hESCs) and differentiated them into human intestinal organoids (HIO). The HES1−/− hESCs retained ES cell properties and showed gene expression patterns similar to those of wild-type hESCs when they differentiated into definitive endoderm and hindgut. During the formation of the HES1−/− lumen we noted an impaired development of mesenchymal cells in addition to the increased differentiation of secretory epithelium. RNA-Seq revealed that inhibited development of the mesenchymal cells may have been due to a downregulation of WNT5A signaling. Overexpression of HES1 and silencing of WNT5A in the intestinal fibroblast cell line CCD-18Co indicated that HES1 was involved in the activation of WNT5A-induced fibroblast growth and migration, suggesting the likelihood of the Notch pathway in epithelial-mesenchymal crosstalk. Our results facilitated the identification of more precise underlying molecular mechanisms displaying distinct roles in HES1 signaling in stromal and epithelial development in human intestinal mucosa.

Auron Therapeutics completes $48 million series A to develop differentiation therapy for cancer

Auron Therapeutics completes $48 million series A to develop differentiation therapy for cancer

IGF2BP2-dependent activation of ERBB2 signaling contributes to acquired resistance to tyrosine kinase inhibitor in differentiation therapy of radioiodine-refractory papillary thyroid cancer.

Acquired drug resistance represents a major obstacle to tyrosine kinase inhibitor (TKI)-induced differentiation therapy of radioiodine-refractory papillary thyroid cancer (RR-PTC); thus, there is an urgent need to elucidate the underlying mechanisms. Here, selumetinib-resistant PTC (PTCSR) cell lines, which were characterized by loss of sodium/iodide symporter expression, enhanced insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), and activated V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2) signaling, were initially established using a dose escalation method. Upon knockdown of IGF2BP2 in PTCSR cells, ERBB2 signaling was inhibited, and the acquired drug resistance was partially reversed. Mechanistically, the luciferase activity assay showed that IGF2BP2 bound to the N6-methyladenosine-binding site in the coding sequence of ERBB2 mRNA, yielding an increased ERBB2 translation efficacy revealed by polysome profiling. Inhibition of ERBB2 and IGF2BP2 by lapatinib robustly rescued the PTCSR cells from acquired dedifferentiation. Our study demonstrated that IGF2BP2-dependent ERBB2 signaling activation contributes to acquired resistance to TKI, which may be a promising differentiation strategy for RR-PTC by targeting IGF2BP2.

Identifying the E2F3-MEX3A-KLF4 signaling axis that sustains cancer cells in undifferentiated and proliferative state.

Rationale: Dysregulation of signaling that governs self-renewal and differentiation of intestinal stem cells (ISCs) is a major cause of colorectal cancer (CRC) initiation and progression.Methods: qRT-PCR, western blotting, in situ hybridization, immunohistochemistry and immunofluorescence assays were used to detect the expression levels of MEX3A, KLF4 and E2F3 in CRC tissues. The biological functions of MEX3A were studied using Mex3a knockout (KO) and intestinal epithelium specific conditional knockout (cKO) mice, AOM-DSS mouse colorectal tumor model, Apc floxed mouse tumor model and intestinal and tumor organoids. Transcriptomic RNA sequencing (RNA-seq), RNA crosslinking immunoprecipitation (CLIP) and luciferase reporter assays were performed to explore the molecular mechanisms of MEX3A.Results: RNA-binding protein MEX3A, a specific ISC marker gene, becomes ectopically upregulated upon CRC and its levels negatively correlate with patient survival prognosis. MEX3A functions as an oncoprotein that retains cancer cells in undifferentiated and proliferative status and it enhances their radioresistance to DNA damage. Mechanistically, a rate limiting factor of cellular proliferation E2F3 induces MEX3A, which in turn activates WNT pathway by directly suppressing expression of its pro-differentiation transcription factor KLF4. Knockdown of MEX3A with siRNA or addition of KLF4 agonist significantly suppressed tumor growth both by increasing differentiation status of cancer cells and by suppressing their proliferation.Conclusions: It identifies E2F3-MEX3A-KLF4 axis as an essential coordinator of cancer stem cell self-renewal and differentiation, representing a potent new druggable target for cancer differentiation therapy.

Regulation of a progenitor gene program by SOX4 is essential for mammary tumor proliferation

In breast cancer the transcription factor SOX4 has been shown to be associated with poor survival, increased tumor size and metastasis formation. This has mostly been attributed to the ability of SOX4 to regulate Epithelial-to-Mesenchymal-Transition (EMT). However, SOX4 regulates target gene transcription in a context-dependent manner that is determined by the cellular and epigenetic state. In this study we have investigated the loss of SOX4 in mammary tumor development utilizing organoids derived from a PyMT genetic mouse model of breast cancer. Using CRISPR/Cas9 to abrogate SOX4 expression, we found that SOX4 is required for inhibiting differentiation by regulating a subset of genes that are highly activated in fetal mammary stem cells (fMaSC). In this way, SOX4 re-activates an oncogenic transcriptional program that is regulated in many progenitor cell-types during embryonic development. SOX4-knockout organoids are characterized by the presence of more differentiated cells that exhibit luminal or basal gene expression patterns, but lower expression of cell cycle genes. In agreement, primary tumor growth and metastatic outgrowth in the lungs are impaired in SOX4KO tumors. Finally, SOX4KO tumors show a severe loss in competitive capacity to grow out compared to SOX4-proficient cells in primary tumors. Our study identifies a novel role for SOX4 in maintaining mammary tumors in an undifferentiated and proliferative state. Therapeutic manipulation of SOX4 function could provide a novel strategy for cancer differentiation therapy, which would promote differentiation and inhibit cycling of tumor cells.

Therapeutically targeting oncogenic CRCs facilitates induced differentiation of NB by RA and the BET bromodomain inhibitor

Retinoic acids (RAs) are the most successful therapeutics for cancer differentiation therapy used in high-risk neuroblastoma (NB) maintenance therapy but are limited in effectiveness. This study identifies a strategy for improving efficacy through disruption of cancer cell identity via BET inhibitors. Mutations that block development are theorized to cause NB through retention of immature cell identities contributing to oncogenesis. NB has two interchangeable cell identities, maintained by two different core transcriptional regulatory circuitries (CRCs): a therapy-resistant mesenchymal/stem cell state and a proliferative adrenergic cell state. MYCN amplification is a common mutation of high-risk NB and recently found to block differentiation by driving high expression of the adrenergic CRC transcription factor ASCL1. We investigated whether disruption of immature CRCs can promote RA-induced differentiation since only a subset of NB patients responds to RA. We found that silencing ASCL1, a critical member of the adrenergic CRC, or global disruption of CRCs with the BET inhibitor JQ1, suppresses gene expression of multiple CRC factors, improving RA-mediated differentiation. Further, JQ1 and RA synergistically decrease proliferation and induce differentiation in NB cell lines. Our findings support preclinical studies of RA and BET inhibitors as a combination therapy in treating NB.

A novel ligand of the translationally controlled tumor protein (TCTP) identified by virtual drug screening for cancer differentiation therapy

SummaryIntroduction Differentiation therapy is a promising strategy for cancer treatment. The translationally controlled tumor protein (TCTP) is an encouraging target in this context. By now, this field of research is still at its infancy, which motivated us to perform a large-scale screening for the identification of novel ligands of TCTP. We studied the binding mode and the effect of TCTP blockade on the cell cycle in different cancer cell lines. Methods Based on the ZINC-database, we performed virtual screening of 2,556,750 compounds to analyze the binding of small molecules to TCTP. The in silico results were confirmed by microscale thermophoresis. The effect of the new ligand molecules was investigated on cancer cell survival, flow cytometric cell cycle analysis and protein expression by Western blotting and co-immunoprecipitation in MOLT-4, MDA-MB-231, SK-OV-3 and MCF-7 cells. Results Large-scale virtual screening by PyRx combined with molecular docking by AutoDock4 revealed five candidate compounds. By microscale thermophoresis, ZINC10157406 (6-(4-fluorophenyl)-2-[(8-methoxy-4-methyl-2-quinazolinyl)amino]-4(3H)-pyrimidinone) was identified as TCTP ligand with a KD of 0.87 ± 0.38. ZINC10157406 revealed growth inhibitory effects and caused G0/G1 cell cycle arrest in MOLT-4, SK-OV-3 and MCF-7 cells. ZINC10157406 (2 × IC50) downregulated TCTP expression by 86.70 ± 0.44% and upregulated p53 expression by 177.60 ± 12.46%. We validated ZINC10157406 binding to the p53 interaction site of TCTP and replacing p53 by co-immunoprecipitation. Discussion ZINC10157406 was identified as potent ligand of TCTP by in silico and in vitro methods. The compound bound to TCTP with a considerably higher affinity compared to artesunate as known TCTP inhibitor. We were able to demonstrate the effect of TCTP blockade at the p53 binding site, i.e. expression of TCTP decreased, whereas p53 expression increased. This effect was accompanied by a dose-dependent decrease of CDK2, CDK4, CDK, cyclin D1 and cyclin D3 causing a G0/G1 cell cycle arrest in MOLT-4, SK-OV-3 and MCF-7 cells. Our findings are supposed to stimulate further research on TCTP-specific small molecules for differentiation therapy in oncology.

The ecology of cancer differentiation therapy

A promising, yet still under development approach to cancer treatment is based on the idea of differentiation therapy (DTH). Most tumours are characterized by poorly differentiated cell populations exhibiting a marked loss of traits associated to communication and tissue homeostasis. DTH has been suggested as an alternative (or complement) to cytotoxic-based approaches, and has proven successful in some specific types of cancer such as acute promyelocytic leukemia (APL). While novel drugs favouring the activation of differentiation therapies are being tested, several open problems emerge in relation to its effectiveness on solid tumors. Here we present a mathematical framework to DTH based on a well-known ecological model used to describe habitat loss. The models presented here account for some of the observed clinical and in vitro outcomes of DTH, providing relevant insight into potential therapy design. Furthermore, the same ecological approach is tested in a hierarchical model that accounts for cancer stem cells, highlighting the role of niche specificity in CSC therapy resistance. We show that the lessons learnt from metapopulation ecology can help guide future developments and potential difficulties of DTH.

Nuclear Receptors as Potential Therapeutic Targets for Myeloid Leukemia.

The nuclear receptor (NR) superfamily has been studied extensively in many solid tumors and some receptors have been targeted to develop therapies. However, their roles in leukemia are less clear and vary considerably among different types of leukemia. Some NRs participate in mediating the differentiation of myeloid cells, making them attractive therapeutic targets for myeloid leukemia. To date, the success of all-trans retinoic acid (ATRA) in treating acute promyelocytic leukemia (APL) remains a classical and unsurpassable example of cancer differentiation therapy. ATRA targets retinoic acid receptor (RAR) and forces differentiation and/or apoptosis of leukemic cells. In addition, ligands/agonists of vitamin D receptor (VDR) and peroxisome proliferator-activated receptor (PPAR) have also been shown to inhibit proliferation, induce differentiation, and promote apoptosis of leukemic cells. Encouragingly, combining different NR agonists or the addition of NR agonists to chemotherapies have shown some synergistic anti-leukemic effects. This review will summarize recent research findings and discuss the therapeutic potential of selected NRs in acute and chronic myeloid leukemia, focusing on RAR, VDR, PPAR, and retinoid X receptor (RXR). We believe that more mechanistic studies in this field will not only shed new lights on the roles of NRs in leukemia, but also further expand the clinical applications of existing therapeutic agents targeting NRs.

Comparison of Survivor Scores for Differentiation Therapy of Cancer to those for Check Point Inhibition.

Differentiation therapy (DT) is directed to the self‐renewing cancer stem cells, as well as their progeny transit amplifying cells, to force them to mature to terminal differentiation. Differentiation therapy is effective in treatment of neuroblastomas and myeloid leukemias. Check point inhibition (CPI) therapy removes blocks to cancer reactive T‐killer cells and allows them to react to malignant cells and limit growth of cancer. The percent of patients with a given cancer that respond to either therapy is less than hoped for and the duration of response is variable. Multiplying the response rate (% of patients responding to therapy) by the duration of response may be used to derive a survival score for patients treated with DT or CPI. By this criterion DT gives better survival scores than CPI. Yet, CPI is considered a great success, mostly because it may be applied to many different types of cancer and DT is considered relatively ineffective because it is limited to a few specific cancers. On the other hand, the cost of CPI treatment is 10 to 20 times more per patient than DT. Hopefully, future combined treatments and advances in both approaches will increase the effectiveness and decrease the cost of these cancer treatments. For example, resent results with combination therapy of melanoma with two check point inhibitors has substantially increased the survival score.Support or Funding InformationNo support

Mebendazole for Differentiation Therapy of Acute Myeloid Leukemia Identified by a Lineage Maturation Index

Accurate assessment of changes in cellular differentiation status in response to drug treatments or genetic perturbations is crucial for understanding tumorigenesis and developing novel therapeutics for human cancer. We have developed a novel computational approach, the Lineage Maturation Index (LMI), to define the changes in differentiation state of hematopoietic malignancies based on their gene expression profiles. We have confirmed that the LMI approach can detect known changes of differentiation state in both normal and malignant hematopoietic cells. To discover novel differentiation therapies, we applied this approach to analyze the gene expression profiles of HL-60 leukemia cells treated with a small molecule drug library. Among multiple drugs that significantly increased the LMIs, we identified mebendazole, an anti-helminthic clinically used for decades with no known significant toxicity. We tested the differentiation activity of mebendazole using primary leukemia blast cells isolated from human acute myeloid leukemia (AML) patients. We determined that treatment with mebendazole induces dramatic differentiation of leukemia blast cells as shown by cellular morphology and cell surface markers. Furthermore, mebendazole treatment significantly extended the survival of leukemia-bearing mice in a xenograft model. These findings suggest that mebendazole may be utilized as a low toxicity therapeutic for human acute myeloid leukemia and confirm the LMI approach as a robust tool for the discovery of novel differentiation therapies for cancer.

Comparison of survivor scores for differentiation therapy of cancer to those for checkpoint inhibition: Half full or half empty.

Differentiation therapy is directed to the self-renewing cancer stem cells, as well as their progeny transit amplifying cells, to force them to mature to terminal differentiation. Differentiation therapy is effective in treatment of neuroblastomas and myeloid leukemias. Checkpoint inhibition therapy removes blocks to cancer reactive T-killer cells and allows them to react to malignant cells and limit the growth of cancer. The percentage of patients with a given cancer that responds to either therapy is less than hoped for, and the duration of response is variable. Multiplying the response rate (percentage of patients responding to therapy) by the duration of response may be used to derive a survival score for patients treated with differentiation therapy or checkpoint inhibition. By this criterion, differentiation therapy gives better survival scores than checkpoint inhibition. Yet, checkpoint inhibition is considered a great success, mostly because it may be applied to many different types of cancer, and differentiation therapy is considered relatively ineffective because it is limited to a few specific cancers. On the other hand, the cost of checkpoint inhibition treatment is 10-20 times more per patient than that of differentiation therapy. Hopefully, future combined treatments and advances in both approaches will increase the effectiveness of these cancer treatments.

Cancer stem cells and differentiation therapy.

Cancer stem cells can generate tumors from only a small number of cells, whereas differentiated cancer cells cannot. The prominent feature of cancer stem cells is its ability to self-renew and differentiate into multiple types of cancer cells. Cancer stem cells have several distinct tumorigenic abilities, including stem cell signal transduction, tumorigenicity, metastasis, and resistance to anticancer drugs, which are regulated by genetic or epigenetic changes. Like normal adult stem cells involved in various developmental processes and tissue homeostasis, cancer stem cells maintain their self-renewal capacity by activating multiple stem cell signaling pathways and inhibiting differentiation signaling pathways during cancer initiation and progression. Recently, many studies have focused on targeting cancer stem cells to eradicate malignancies by regulating stem cell signaling pathways, and products of some of these strategies are in preclinical and clinical trials. In this review, we describe the crucial features of cancer stem cells related to tumor relapse and drug resistance, as well as the new therapeutic strategy to target cancer stem cells named "differentiation therapy."

Alternol inhibits the proliferation and induces the differentiation of the mouse melanoma B16F0 cell line

High malignant potential and low susceptibility to treatment are characteristics of malignant melanoma. Alternol, a novel compound purified from microbial fermentation products obtained from the bark of the yew tree, exhibits a variety of antitumor activities. Based on these findings, the aim of the present study was to extend the knowledge on the antineoplastic effect of alternol in the mouse melanoma B16F0 cell line. Alternol significantly inhibited the proliferation and colony formation of B16F0 cells in a dose-dependent manner as detected by MTT and soft agar colony formation assays. NaOH alkaline lysis and oxidation of Dopa indicated that alternol enhanced the melanin content and tyrosinase activity of the B16F0 cells and results also showed a dose‑response relationship. Morphologic changes accompanied by extended dendrites were discovered in the B16F0 cells after treatment with alternol. Furthermore, the mRNA levels of tyrosinase, Trp1 and Trp2 were increased by alternol. Our results confirmed that alternol possesses marked antineoplastic properties against melanoma cells, indicating that this microbial fermentation product is a promising agent for the differentiation therapy of cancer. The inhibition of cell proliferation and colony formation by alternol was associated with both cytotoxicity and induction of differentiation.

Interaction of antihistaminic drugs with human translationally controlled tumor protein (TCTP) as novel approach for differentiation therapy.

Translationally controlled tumor protein (TCTP) represents an exquisite target for cancer differentiation therapy, because it was most strikingly down-regulated in tumor reversion experiments. Since TCTP is identical with the histamine releasing factor, antihistamic drugs may inhibit TCTP. Indeed, antihistaminics, such as promethazine, thioridazine, perphemazine and chlorpromazine reveal antiproliferative effects. The aim of this investigation was to study antihistaminic drugs as new TCTP inhibitors to inhibit tumor growth. Levomepromazine and buclizine showed higher in silico binding affinities to TCTP among 12 different antihistaminic compounds including the control drugs, promethazine and hydroxyzine by using Autodock4 and AutodockTools-1.5.7.rc1. Recombinant human TCTP was codon-optimized, expressed in E. coli and purified by chitin affinity chromatography. For experimental validation of in silico data, we applied microscale thermophoresis. Levomepromazine bound with a Kd of 57.2 μM (p < 0.01) and buclizine with a Kd of 433μM (p < 0.01) to recombinant TCTP. Both drugs inhibited MCF-7 breast cancer cell growth in resazurin assays. TCTP expression was down-regulated after treatment with the two drugs. Cell cycle was arrested in the G1 phase without apoptosis as confirmed by the expression of cell cycle and apoptosis-regulating proteins. Annexin V-PI staining and Trypan blue exclusion assay supported that the two drugs are cytostatic rather than cytotoxic. Induction of differentiation with two drugs was detected by the increased appearance of lipid droplets. In conclusion, levomepromazine and buclizine inhibited cancer cell growth by binding to TCTP and induction of cell differentiation. These compounds may serve as lead compounds for cancer differentiation therapy.

Abstract B2-12: A systems biology approach for the discovery of differentiation therapeutics

Abstract Accurately assessing the changes in cellular differentiation status in response to drug treatments or genetic manipulations is crucial for understanding the tumorigenesis process and developing novel therapeutics for human cancer. Here we have developed a novel systems biology approach, called the Lineage Maturation Index (LMI), to define the changes in differentiation state of cancer cells based on their gene expression profiles. We have been focusing on hematopoietic malignancies, but this approach is applicable to many human cancer types. We define the expression profile of N genes within a cell to be a point in an N-dimensional space. A lineage vector is derived from a progenitor cell (such as a hematopoietic stem cell) to a mature cell (such as a granulocyte) based on the expression of these N genes. By projecting the expression profile of an unknown cell onto the lineage vector, an LMI can be computed for the differentiation state of this specific cell. Upon drug treatments or genetic manipulations, a shift in LMI from stem cells towards mature cell types indicates differentiation. We have confirmed that the LMI approach can track the differentiation of normal hematopoietic cells. We have further shown that differentiation is a major consequence of various targeted therapies against leukemia irrespective of the driving oncogenes. Most importantly, we have used this approach to analyze the Connectivity Map HL60 leukemia data set for drugs that can induce leukemia cells to differentiate. In addition to drugs known to have differentiation activities (such as all-trans retinoic acid and etoposide), we discovered that several novel drugs (such as dihydroergotamine, mebendazole, and clonidine) have potent differentiation activities in leukemia cells. Currently, we are expanding our study into multiple types of solid tumors, such as breast, prostate, and colon cancers. Our LMI approach is highly robust in characterizing differentiation of the cancer cells and discovering novel differentiation therapies for human cancer. Citation Format: Yulin Li, Jun Seita, Dean Felsher, David L. Dill. A systems biology approach for the discovery of differentiation therapeutics. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B2-12.

Abstract A2-35: Discovery of differentiation therapeutics using a systems biology approach

Abstract Accurately assessing the changes in cellular differentiation status in response to drug treatments or genetic manipulations is crucial for understanding the tumorigenesis process and developing novel therapeutics for human cancer. Here we have developed a novel systems biology approach, called the Lineage Maturation Index (LMI), to define the changes in differentiation state of cancer cells based on their gene expression profiles. We have been focusing on hematopoietic malignancies, but this approach is applicable to many human cancer types. We define the expression profile of N genes within a cell to be a point in an N-dimensional space. A lineage vector is derived from a progenitor cell (such as a hematopoietic stem cell) to a mature cell (such as a granulocyte) based on the expression of these N genes. By projecting the expression profile of an unknown cell onto the lineage vector, an LMI can be computed for the differentiation state of this specific cell. Upon drug treatments or genetic manipulations, a shift in LMI from stem cells towards mature cell types indicates differentiation. We have confirmed that the LMI approach can track the differentiation of normal hematopoietic cells. We have further shown that differentiation is a major consequence of various targeted therapies against leukemia irrespective of the driving oncogenes. Most importantly, we have used this approach to analyze the Connectivity Map HL60 leukemia data set for drugs that can induce leukemia cells to differentiate. In addition to drugs known to have differentiation activities (such as all-trans retinoic acid and etoposide), we discovered that several novel drugs (such as dihydroergotamine, mebendazole, and clonidine) have potent differentiation activities in leukemia cells. Currently, we are expanding our study into multiple types of solid tumors, such as breast, prostate, and colon cancers. Our LMI approach is highly robust in characterizing differentiation of the cancer cells and discovering novel differentiation therapies for human cancer. Citation Format: Yulin Li, Jun Seita, Dean Felsher, David Dill. Discovery of differentiation therapeutics using a systems biology approach. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-35.