Praneeth Reddy Sudalagunta

Moffitt Cancer Center · Department of Cancer Imaging and Metabolism (CIM)

Multiple myeloma (MM) is an incurable disease. Classical chemotherapeutics including bortezomib, melphalan, lenalidomide and thalidomide have greatly enhanced survival times. Unfortunately, patients typically relapse and become refractory with an average survival of 5 years post-diagnosis. Our emerging studies demonstrate a novel role for ULK3 in r...

Motivation Time-lapse microscopy is a powerful technique that relies on images of live cells cultured ex vivo that are captured at regular intervals of time to describe and quantify their behavior under certain experimental conditions. This imaging method has great potential in advancing the field of precision oncology by quantifying the response o...

The clinical utility of histone/protein deacetylase (HDAC) inhibitors (HDACi's) in combinatorial regimens with proteasome inhibitors for patients with relapsed and refractory multiple myeloma (MM) is limited often by excessive toxicity due to HDACi promiscuity with multiple HDACs. Therefore, more selective inhibition minimizing off-target toxicity...

Interactions between the IAP antagonist LCL161 and the histone deacetylase inhibitor (HDACI) panobinostat (LBH589) were examined in human multiple myeloma (MM) cells. LCL161 and panobinostat interacted synergistically to induce apoptosis in diverse MM cell lines including those resistant to bortezomib (PS-R). Similar interactions were observed with...

Introduction. Multiple myeloma (MM) is an all but incurable plasma cell malignancy without predictive biomarkers for approved therapies. Selinexor (SELI), a nuclear export inhibitor targeting exportin 1 (XPO1), is approved with dexamethasone (DEX) with promising SELI-combination studies ongoing. We investigated SELI combinations ex vivo to identify...

The plasma cell malignancy multiple myeloma (MM) evolves from a pre-malignant state and remains all but incurable due to emergence of therapy resistance. Despite intensive analyses, mechanisms driving MM progression and refractory disease are poorly understood. Integrating topologic, expression and epigenetic analyses of 1,016 patient specimens, we...

Multiple myeloma (MM) is an incurable cancer of bone marrow-resident plasma cells, which evolves from a premalignant state, MGUS, to a form of active disease characterized by an initial response to therapy, followed by cycles of therapeutic successes and failures, culminating in a fatal multi-drug resistant cancer. The molecular mechanisms leading...

Introduction. Multiple myeloma (MM) is an incurable plasma cell malignancy with a growing list of anti-MM therapeutics. However, the development of predictive biomarkers has yet to be achieved for nearly all MM therapeutics. Selinexor (SELI), a nuclear export inhibitor targeting exportin 1 (XPO1), has been approved with dexamethasone (DEX) in penta...

Introduction: Despite some long-term remissions, eventual drug resistance in most patients remains a critical obstacle in the treatment of multiple myeloma (MM). The development of new drugs/drug combinations with novel mechanisms of action are needed for continued improvement in patient outcomes. Initiation of tumor cell death via activation of th...

Time-lapse microscopy is a powerful technique that generates large volumes of image-based information to quantify the behaviors of cell populations. This method has been applied to cancer studies to estimate the drug response for precision medicine and has great potential to address inter-patient (or intertumoral) heterogeneity. A couple of algorit...

Background Multiagent therapies, due to their ability to delay or overcome resistance, are a hallmark of treatment in multiple myeloma (MM). The growing number of therapeutic options in MM requires high-throughput combination screening tools to better allocate treatment, and facilitate personalized therapy. Methods A second-order drug response mod...

Multiple Myeloma (MM) remains an incurable malignancy, despite the advent of several new therapeutic agents, including immunomodulatory drugs (IMiDs, e.g., Lenalidomide (Len)) and proteasome inhibitors (PIs, e.g., Bortezomib (Btz)). Accordingly, there is an urgent need to identify new targetable vulnerabilities for MM patients. We developed an ex v...

Problem: Multiple myeloma (MM) is a treatable yet incurable hematologic cancer that lacks predictive biomarkers. Approach: Here we apply a systems biology approach to determine patient-specific mechanisms, as well as signatures of drug resistance in MM. To achieve this goal, we have combined ex vivo drug sensitivity data from 307 MM fresh primary s...

Introduction The use of proteasome inhibitors (PIs), such as bortezomib (BTZ), in multiple myeloma (MM) has markedly increased the survival of newly diagnosed patients. Although advancements in therapeutic regimens in the past decade have improved prognosis, we lack knowledge of the mechanisms that lead to drug resistance. To assess the contributor...

Over the last decade we have witnessed an explosion in the number of therapeutic options available to patients with multiple myeloma (MM). In spite of the marked improvements in patient outcomes paralleling these approvals, MM remains an incurable malignancy for the vast majority of patients following a course of therapeutic successes and failures....

e19513 Background: Although there is much to be optimistic about in the multiple myeloma community as the approval of new therapies and regimen-combinations for relapsed refractory disease continues to grow, determining the best option for a patient can be complicated. Both carfilzomib- (C) and daratumumab- (D) based regimens have demonstrated supe...

Drug-tolerant "persister" tumor cells underlie emergence of drug-resistant clones and contribute to relapse and disease progression. Here we report that resistance to the BCL-2 targeting drug ABT-199 in models of mantle cell lymphoma and double-hit lymphoma evolves from outgrowth of persister clones displaying loss of 18q21 amplicons that harbor BC...

Proteasome inhibitors (PI) such as bortezomib and carfilzomib are critical components of anti-multiple myeloma (MM) therapy, yet all MM patients eventually develop refractory disease. We developed a non-biased method to identify and validate dysregulated pathways associated with PI-resistance in myeloma by combining RNAseq data from 522 MM patient...

We describe an approach to identify patient-specific mechanisms of drug resistance in multiple myeloma (MM) patients through a combination of ex vivo chemosensitivity assay using fresh primary samples and gene set enrichment analysis from RNA-Seq and microarray gene expression profiles. Methods: We have performed RNA-Seq on 522 primary MM samples a...

Background: c-MYC is a transcription factor that promotes oncogenesis by activating and repressing its target genes that control cell growth, metabolism, and proliferation. MYC is deregulated in a large proportion of aggressive B-cell lymphomas. A typical example is the Double-Hit Lymphoma (DHL) and Double-Expression Lymphoma (DEL) which present wi...

Introduction: Innate and acquired resistance to anti-cancer therapies poses a major hurdle in effectively treating many cancers, especially an incurable cancer like multiple myeloma (MM). Rational combination therapies have shown improved efficacy and reduced toxicity in MM. Patient variability in response to single agents leads to variability in c...

Concordant activation of MYC and BCL-2 oncoproteins in double-hit lymphoma (DHL) results in aggressive disease that is refractory to treatment. By integrating activity-based proteomic profiling and drug screens, polo-like kinase-1 (PLK1) was identified as an essential regulator of the MYC-dependent kinome in DHL. Notably, PLK1 was expressed at high...

Modeling aeroelastic effects for an airbreathing hypersonic vehicle is challenging due to its tightly integrated airframe and propulsion system that leads to significant deflections in the thrust vector caused by flexing of the airframe. These changes in the orientation of the thrust vector in turn introduce low-frequency oscillations in the flight...

Multiple myeloma (MM) remains treatable but incurable. Despite a growing armamentarium of effective agents, choice of therapy, especially in relapse, still relies almost exclusively on clinical acumen. We have developed a system, EMMA (Ex vivo Mathematical Myeloma Advisor), consisting of patient-specific mathematical models parameterized by an ex v...

Motivated by the need for high-fidelity modeling and accurate control of future hypersonic vehicles subjected to complex aerothermomechanical loads and many other such applications, a novel scheme is proposed to accurately compute higher modes of vibration for one-dimensional structures by coupling the classic Ritz method as a predictor and the lin...

Motivated by the control of future hypersonic vehicles subjected to complex aero-thermo-mechanical loads and many other such applications, we propose a novel scheme to compute higher modes of vibration accurately for one-dimensional stuctures, that couples the classic Ritz method as a predictor and the linear two-point boundary value problem (BVP)...