Bindu Santhamma - Academia.edu (original) (raw)

Papers by Bindu Santhamma

Cancer Research

Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease. TNBC lacks targeted ... more Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease. TNBC lacks targeted therapies and represents a disproportional share of the breast cancer (BC) mortality rate. Histone deacetylase inhibitors (HDACIs) are emerging as promising multifunctional agents in TNBC to elicit cytotoxic actions. Recent studies have shown that cancer cells elucidate feedback activation of leukemia inhibitory factor receptor (LIFR) which in turn curtails response to HDACIs. We developed a first-in-class inhibitor of LIFR, EC359 that directly interacts with LIFR and effectively blocks LIFR downstream signaling. Here, we examined whether the novel LIFR inhibitor, EC359, has the ability to counteract negative effects of LIFR signaling to enhance HDACIs therapeutic efficacy in the treatment of TNBC. Methods: We tested multiple HDACIs currently in clinical trials including vorinostat, panobinostat, romidepsin, and givinostat using multiple TNBC models. The effect of combination therapy of ...

Communications Biology, 2021

Histone deacetylase inhibitors (HDACi) are identified as novel therapeutic agents, however, recen... more Histone deacetylase inhibitors (HDACi) are identified as novel therapeutic agents, however, recent clinical studies suggested that they are marginally effective in treating triple negative breast cancer (TNBC). Here, we show that first-in-class Leukemia Inhibitory Factor Receptor (LIFRα) inhibitor EC359 could enhance the therapeutic efficacy of HDACi against TNBC. We observed that both targeted knockdown of LIFR with CRISPR or treatment with EC359 enhanced the potency of four different HDACi in reducing cell viability, cell survival, and enhanced apoptosis compared to monotherapy in TNBC cells. RNA-seq studies demonstrated oncogenic/survival signaling pathways activated by HDACi were attenuated by the EC359 + HDACi therapy. Importantly, combination therapy potently inhibited the growth of TNBC patient derived explants, cell derived xenografts and patient-derived xenografts in vivo. Collectively, our results suggest that targeted inhibition of LIFR can enhance the therapeutic efficac...

Scientific Reports, 2019

Uterine fibroids (UFs) are associated with irregular or excessive uterine bleeding, pelvic pain o... more Uterine fibroids (UFs) are associated with irregular or excessive uterine bleeding, pelvic pain or pressure, or infertility. Ovarian steroid hormones support the growth and maintenance of UFs. Ulipristal acetate (UPA) a selective progesterone receptor (PR) modulator (SPRM) reduce the size of UFs, inhibit ovulation and lead to amenorrhea. Recent liver toxicity concerns with UPA, diminished enthusiasm for its use and reinstate the critical need for a safe, efficacious SPRM to treat UFs. In the current study, we evaluated the efficacy of new SPRM, EC313, for the treatment for UFs using a NOD-SCID mouse model. EC313 treatment resulted in a dose-dependent reduction in the fibroid xenograft weight (p < 0.01). Estradiol (E2) induced proliferation was blocked significantly in EC313-treated xenograft fibroids (p < 0.0001). Uterine weight was reduced by EC313 treatment compared to UPA treatment. ER and PR were reduced in EC313-treated groups compared to controls (p < 0.001) and UPA t...

Journal of Molecular Cell Biology, 2020

Cancer Research, 2020

Background: Triple-negative breast cancer (TNBC) lacks targeted therapies and represents a dispro... more Background: Triple-negative breast cancer (TNBC) lacks targeted therapies and represents a disproportional share of the breast cancer (BC) mortality rate. TNBC exhibits autocrine stimulation of the LIF/LIFR axis and overexpression of LIF is associated with poorer relapse-free survival in BC patients. Histone deacetylase inhibitors (HDACIs) are emerging as promising multifunctional agents in TNBC to elicit cytotoxic actions. Recent studies have shown that cancer cells elicit feedback activation of leukemia inhibitory factor receptor (LIFR) which in turn curtails response to HDACIs. We developed a first-in-class inhibitor of LIFR, EC359 that directly interacts with LIFR and effectively blocks LIFR downstream signaling. The objective of this study is to examine the therapeutic efficacy of combination therapy using preclinical and patient-derived xenograft (PDX) models. Methods: We tested utility of combination therapy using multiple HDACIs that are currently in clinical trails along wi...

Molecular Cancer Therapeutics, 2018

Background: An IL-6 family member, leukemia inhibitory factor (LIF), is a pleotropic cytokine inv... more Background: An IL-6 family member, leukemia inhibitory factor (LIF), is a pleotropic cytokine involved in multiple cellular signaling and pathophysiology of various malignancies including cancer. Overexpression of LIF is significantly correlated with advanced tumor stage, larger tumor size and worse relapse free survival rate. The objective of present study to develop and characterize next generation steroidal LIF/LIFR inhibitor based on our first LIF inhibitor, EC330. In this study, we optimized EC330 by synthetic modifications and generated EC359 to reduce its binding to classical steroid receptors and to improve its oral bioavailability. Material and methods: In silico docking studies were used to identify putative interaction of EC359 and LIF/LIFR receptor complex. We confirmed binding of EC359 to LIFR using surface plasmon resonance (SPR). Biophysical and biological characterization was performed by measuring cytotoxicity in various cancer cell lines and anchorage-independent c...

Steroids, 2018

An effort with the goal of discovering single-dose, long-lasting (> 6 months) injectable contrace... more An effort with the goal of discovering single-dose, long-lasting (> 6 months) injectable contraceptives began using levonorgestrel (LNG)-17-β esters linked to a sulfonamide function purposed as human carbonic anhydrase II (hCA 2) ligands. One single analog from this first series showed noticeably superior anti-ovulatory activity in murine models, and a subsequent structure-activity relationship (SAR, the relationship between a compound's molecular structure and its biological activity) study based on this compound identified a LNG-phenoxyacetic acid ester analog exhibiting longer anti-ovulatory properties using the murine model at 2 and 4 mg dose than medroxyprogesterone acetate (MPA). The same ester function linked to etonogestrel (ENG) furnished a compound which inhibited ovulation at 2 mg for 60 days, the longest duration of all compounds tested at these doses. By comparison, MPA at the same dose inhibited ovulation for 32 days.

Molecular and Cellular Biology / Genetics, 2019

Ovarian cancer (OCa) is the deadliest of all gynecologic cancers in the United States and a criti... more Ovarian cancer (OCa) is the deadliest of all gynecologic cancers in the United States and a critical need exists for the development of novel therapies for the treatment of OCa. Leukemia inhibitory factor receptor (LIFR) and its ligand LIF play a critical role in cancer progression, metastasis, stem cell maintenance, and therapy resistance. Recent clinical studies showed that cancer cells elucidate feedback activation of LIFR that limits response to histone deacetylase (HDAC) inhibitors. Recently, we developed a first-in-class inhibitor of LIFR, EC359 that directly interacts with LIFR and effectively blocks LIF-LIFR interactions. Here, we examined whether LIFR inhibitor EC359 abrogate the side effects of histone deacetylase inhibitor SAHA (Vorinostat) for the treatment of OCa. Methods: The effect of EC359 and SAHA as a combination therapy on OCa cell viability was examined by MTT assays. The efficacy of combination therapy on cell survival and apoptosis was determined using clonogenic assays and caspase3/7 assays respectively. The efficacy of combination therapy on OCa stem cells was determined using extreme limiting dilution assays. Mechanistic studies were performed using western blotting, qRT-PCR and Mass Spectrometry analyses. The effect of combination therapy on STAT3 signaling was examined using reporter gene assays. The in vivo efficacy of combination therapy on tumors was examined using ex vivo patient derived explants and mouse xenograft models. Results: EC359 significantly enhanced the efficacy of SAHA in reducing cell viability, colony formation ability, and apoptosis compared to monotherapy of SAHA in multiple established and primary OCa cells. Further, EC359 enhanced SAHA ability to reduce self-renewal of OCa stem cells. As expected in STAT3 reporter assays, SAHA treatment activated STAT3 reporter and EC359 addition abrogated SAHA mediated STAT3 activation. Mechanistic studies using multiple OCa models and western blot analysis confirmed activation of LIFR signaling pathway upon SAHA treatment and its blockage by EC359 treatment. Treatment of human primary OCa tumor explants with EC359 enhanced ability of SAHA to decrease the proliferation (Ki-67 positivity) compared to monotherapy treated tumors. DIA based Mass Spectrometry analyses identified unique pathways modulated by combination therapy. Treatment of OCa xenografts with EC359 enhanced the ability of SAHA to reduce in vivo tumor growth compared to monotherapy treated tumors. Conclusions: Our results suggest that EC359 has therapeutic utility in overcoming the limitation of feedback activation of LIFR observed in the treatment of HDAC inhibitors in treating OCa. Citation Format: Mengxing Li, Suryavathi Viswanadhapalli, Gangadhara Reddy Sareddy, Bindu Santhamma, Hui Yan, Zhenming Xu, Edward Kost, Rajeshwar Rao Tekmal, Hareesh B. Nair, Klaus J. Nickisch, Ratna K. Vadlamudi. Targeting LIFR overcomes HDAC inhibitor resistance in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4316.

Experimental and Molecular Therapeutics, 2019

Background: Leukemia inhibitory factor receptor (LIFR) and its ligand LIF play a major critical r... more Background: Leukemia inhibitory factor receptor (LIFR) and its ligand LIF play a major critical role in cancer progression, metastasis, stem cell maintenance, and therapy resistance. Recent studies in breast cancer have shown that feedback activation of LIFR limits response to histone deacetylase (HDAC) inhibitors and induce resistance. We rationally designed a small molecule (EC359) that emulates the LIF-LIFR binding site and functions as a LIFR inhibitor from a library of compounds. Here, we tested the utility of EC359 as a monotherapy and to effectively block LIF-LIFR interactions in overcoming resistance to HDAC inhibitors. Methods: We have used multiple triple negative breast cancer (TNBC) models that represent all six types of TNBC. In vitro activity was tested using Cell-Titer Glo, MTT, invasion, and apoptosis assays. Mechanistic studies were conducted using western blot, reporter gene assays, and RNA-seq analysis. Xenograft, patient-derived xenograft (PDX), and patient-derived explant (PDeX) models were used for preclinical evaluation and toxicity. Results: EC359 treatment exhibited anti-proliferative effects, reduced invasiveness and stemness, and promoted apoptosis in all six TNBC cell lines. The activity of EC359 is dependent on LIF and LIFR expression and CRISPR mediated knockdown of LIFR significantly abolished EC359 activity. Treatment with EC359 attenuated the activation of LIF-LIFR driven pathways including STAT3, mTOR, and AKT. EC359 significantly reduced tumor progression in TNBC xenografts, PDX models and reduced proliferation in patient derived primary TNBC explants. In MTT based cell viability assays, addition of EC359 enhanced efficacy of SAHA compared to monotherapy of SAHA. In clonogenic survival assays, EC359 significantly enhanced ability of SAHA to reduce the colony formation compared to monotherapy. Mechanistic studies using three different TNBC models using western blot analysis and reporter gene assays confirmed activation of LIFR signaling pathway upon SAHA treatment and its blockage by EC359. Treatment of TNBC PDX explants with EC359 enhanced ability of SAHA to substantially decrease the proliferation (Ki-67 positivity) compared to monotherapy treated tumors. Conclusions: Collectively, these data support EC359 as a novel targeted therapeutic that inhibits LIFR oncogenic signaling as a monotherapy or in combination with HDAC inhibitors. Citation Format: Suryavathi Viswanadhapalli, Mengxing Li, Yiliao Luo, Gangadhara R Sareddy, Bindu Santhamma, Mei Zhou, Shihong Ma, Rajni Sonavane, Uday P. Pratap, Kristin A. Altwegg, Annabel Chang, Alejandra Chavez-Riveros, Kalarickal V. Dileep, Kam Y. Zhang, Marek Bajda, Ganesh V. Raj, Andrew Brenner, Vijaya Manthati, Manjeet Rao, Rajeshwar R. Tekmal, Hareesh B. Nair, Klaus J. Nickisch, Ratna K. Vadlamudi. Therapeutic utility of EC359 for targeting oncogenic LIFR signaling in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4716.

How to use the pure antagonists, such as those for the imidazolyl compound and gynecological symp... more How to use the pure antagonists, such as those for the imidazolyl compound and gynecological symptoms and breast cancer, which acts as a pure anti-progestin are described herein.

Cancer Research, 2015

Significant increase in the breast cancer risk reported from the Women’s health initiative (WHI) ... more Significant increase in the breast cancer risk reported from the Women’s health initiative (WHI) study and other clinical studies in postmenopausal women lead to a significantly reduced usage of estrogen/ progestin based HRT treatment in women. A new and interesting approach to provide women with an effective treatment for vasomotor symptoms without an increased breast cancer risk has been reported in preclinical and clinical studies. A combination of conjugated estrogens (CE) + selective estrogen receptor modulator (SERM), bazedoxifene (BZA) offers an effective treatment for overcoming vasomotor symptoms but preventing the proliferation of breast tissue. However, this treatment also has some drawbacks. A higher rate of induced endometrial hyperplasia due to unopposed estroginicity with BZA+ CE treatment regimen has been noted in recent randomized clinical trials. In addition, the risk of venous thromboembolic events has been shown not avoided completely in women who were older at the time of BZE+CE treatment compared with those who were younger. Therefore an unmet need for new HRT regiments that combine effective treatment of symptoms without increasing the risk of breast cancer in postmenopausal women. A potential approach is the combination of estradiol with a partial agonistic antiproprgestin (mesoprogstin or SPRM). In order to test the hypothesis we have compared the combinatory effect of BZA with estrogen (E2) as well as a novel SPRM, EC312+ E2 in a cell culture model of postmenopausal breast cancer. In our model, we have found that the antiestrogenic effect of BZA on T47D cell growth was comparable that of EC312. Both EC312 and BZA increased apoptosis dose dependently in the presence of E2 as well as reduced E2 mediated BrdU incorporation as a read out of cell proliferation. E2 (1nM) treatment increased the expression of anti-apoptotic genes whereas 100nM treatment of EC312 and BZA decreased the levels of anti-apoptotic genes. Expression of E2 stimulated effect on target genes such as cMyc, pS2 and Cyclin D1 were reduced with the treatment of EC312 or BZA. It is evident from our study that EC312 as a novel SPRM exerted no agonistic effects on human breast cancer cells and effectively blocked the stimulatory actions of E2 or conjugated estrogens. The in vitro molecular characterization of EC312 was performed using gene transactivation assays and confirmation of EC312 as a PRM was determined in cycling guinea pig model. Our future animal model with breast cancer xenografts will underscore the possibility of using EC312 as a safer SPRM that antagonize the growth promotional effect of estrogens as well as eliminating the increased breast cancer risk of progestin component of MHT. Further rationale for choosing SPRM/mesoprogestin such as EC312 would stabilize the uterine tissue and endometrium to minimize the oligo-menorrhea and endometrial hyperplasia associated with MHT. Citation Format: Hareesh B Nair, Bindu Santhamma, Walter Elger, Klaus J Nickisch. Effect of a novel selective progesterone receptor modulator EC312 for menopausal hormone therapy (MHT) in comparison with Bazedoxifene in vitro [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-05-08.

Steroids, 2015

A general methodology for the synthesis of different steroidal 17-spirolactones is described. Thi... more A general methodology for the synthesis of different steroidal 17-spirolactones is described. This method uses lithium acetylide of ethyl propiolate as the three carbon synthon and the method was successfully applied for the process development of drospirenone.

Steroids, 2013

A range of 6-, 7-, and 11-substituted estradiols were synthesized by the selective aromatization ... more A range of 6-, 7-, and 11-substituted estradiols were synthesized by the selective aromatization of the Aring of 19-nor steroids using phenylselenyl halides followed by oxidation with hydrogen peroxide. Established methods utilizing copper(II) halides failed or have given poor yields with these substrates.

Synthesis, 2003

ABSTRACT For Abstract see ChemInform Abstract in Full Text.

Organic Letters, 2005

[reaction: see text] Two unprecedented multicomponent reactions of N-heterocyclic carbenes involv... more [reaction: see text] Two unprecedented multicomponent reactions of N-heterocyclic carbenes involving activated acetylenes and aldehydes are described.

Organic Letters, 2004

Cyclopentane derivatives Cyclopentane derivatives Q 0030 A Novel Multicomponent Reaction Involvin... more Cyclopentane derivatives Cyclopentane derivatives Q 0030 A Novel Multicomponent Reaction Involving Isocyanide, Dimethyl Acetylenedicarboxylate (DMAD), and Electrophilic Styrenes: Facile Synthesis of Highly Substituted Cyclopentadienes.-The title three-component one-pot reaction for the synthesis of fully substituted cyclopentadiene derivatives from alkyl isocyanides, (III), and various activated styrenes is developed. All three components of the reaction are variable, thus making it a versatile process.-(NAIR*, V.;

The Journal of Organic Chemistry, 2006

The zwitterion formed by the reaction of dimethoxycarbene and DMAD adds efficiently to one of the... more The zwitterion formed by the reaction of dimethoxycarbene and DMAD adds efficiently to one of the carbonyl groups of 1,2-dicarbonyl compounds and anhydrides to generate dihydrofurans and spirodihydrofurans in good yields. In many cases, the carbene inserts into the C-C bond of the dione to yield masked vicinal tricarbonyl systems.

Breast Cancer Research, 2009

Introduction Proteasome inhibition provides an attractive approach to cancer therapy and may have... more Introduction Proteasome inhibition provides an attractive approach to cancer therapy and may have application in the treatment of breast cancer. However, results of recent clinical trials to evaluate the effect of the proteasome inhibitor Bortezomib (Velcade ® , also called PS-341) in metastatic breast cancer patients have shown limited activity when used as a single agent. This underscores the need to find new and more efficacious proteasome inhibitors. In this study, we evaluate the efficacy of the novel proteasome inhibitor BU-32 (NSC D750499-S) using in vitro and in vivo breast cancer models. Methods We have recently synthesized a novel proteasome inhibitor (BU-32) and tested its growth inhibitory effects in different breast cancer cells including MCF-7, MDA-MB-231, and SKBR3 by in vitro cytotoxicity and proteasomal inhibition assays. The apoptotic potential of BU32 was tested using flow cytometry and analyzing cell cycle regulatory proteins. In vivo tumor xenograft studies for solid tumor as well as tumor metastasis were conducted using MDA-MB-231-GFP cells. Results We report for the first time that BU-32 exhibits strong cytotoxicity in a panel of cell lines: MDA-MB-231 (IC 50 = 5.8 nM), SKBR3 (IC 50 = 5.7 nM) and MCF-7 cells (IC 50 = 5.8 nM). It downregulates a wide array of angiogenic marker genes and upregulates apoptotic markers, including Bid and Bax. Incubation of MDA-MB-231 cells with BU-32 results in the accumulation of cell cycle inhibitor proteins p21 and p27 and stabilization of the tumor suppressor protein p53. Studies in in vivo solid tumor and metastasis models show significant effect with a 0.06 mg/kg dose of BU-32 and marked reduction in tumor burden in the skeleton. Conclusions We have shown that BU-32 is effective in cultured breast cancer cells and in breast cancer xenografts. The results suggest its potential benefit in breast cancer treatment.

Molecular Cancer Therapeutics, 2019

Leukemia inhibitory factor receptor (LIFR) and its ligand LIF play a critical role in cancer prog... more Leukemia inhibitory factor receptor (LIFR) and its ligand LIF play a critical role in cancer progression, metastasis, stem cell maintenance, and therapy resistance. Here, we describe a rationally designed first-in-class inhibitor of LIFR, EC359, which directly interacts with LIFR to effectively block LIF/LIFR interactions. EC359 treatment exhibits antiproliferative effects, reduces invasiveness and stemness, and promotes apoptosis in triple-negative breast cancer (TNBC) cell lines. The activity of EC359 is dependent on LIF and LIFR expression, and treatment with EC359 attenuated the activation of LIF/LIFR-driven pathways, including STAT3, mTOR, and AKT. Concomitantly, EC359 was also effective in blocking signaling by other LIFR ligands (CTF1, CNTF, and OSM) that interact at LIF/LIFR interface. EC359 significantly reduced tumor progression in TNBC xenografts and patient-derived xenografts (PDX), and reduced proliferation in patient-derived primary TNBC explants. EC359 exhibits distin...