Optimal Combination Therapy Research Articles

Ferroptosis and EMT resistance in cancer: a comprehensive review of the interplay.

Ferroptosis differs from traditional cell death mechanisms like apoptosis, necrosis, and autophagy, primarily due to its reliance on iron metabolism and the loss of glutathione peroxidase activity, leading to lipid peroxidation and cell death. The dysregulation of iron metabolism is a hallmark of various cancers, contributing to tumor progression, metastasis, and notably, drug resistance. The acquisition of mesenchymal characteristics by epithelial cells is known as Epithelial-Mesenchymal Transition (EMT), a biological process intricately linked to cancer development, promoting traits such as invasiveness, metastasis, and resistance to therapeutic interventions. EMT plays a pivotal role in cancer progression and contributes significantly to the complex dynamics of carcinogenesis. Research findings indicate that mesenchymal cancer cells exhibit greater susceptibility to ferroptosis compared to their epithelial counterparts. The induction of ferroptosis becomes more effective in eliminating drug-resistant cancer cells during the process of EMT. The interplay between ferroptosis and EMT, a process where epithelial cells transform into mobile mesenchymal cells, is crucial in understanding cancer progression. EMT is associated with increased cancer metastasis and drug resistance. The review delves into how ferroptosis and EMT influence each other, highlighting the role of key proteins like GPX4, which protects against lipid peroxidation, and its inhibition can induce ferroptosis. Conversely, increased GPX4 expression is linked to heightened resistance to ferroptosis in cancer cells. Moreover, the review discusses the implications of EMT-induced transcription factors such as Snail, Zeb1, and Twist in modulating the sensitivity of tumor cells to ferroptosis, thereby affecting drug resistance and cancer treatment outcomes. Targeting the ferroptosis pathway offers a promising therapeutic strategy, particularly for tumors resistant to conventional treatments. The induction of ferroptosis in these cells could potentially overcome drug resistance. However, translating these findings into clinical practice presents challenges, including understanding the precise mechanisms of ferroptosis induction, identifying predictive biomarkers, and optimizing combination therapies. The review underscores the need for further research to unravel the complex interactions between ferroptosis, EMT, and drug resistance in cancer. This could lead to the development of more effective, targeted cancer treatments, particularly for drug-resistant tumors, offering new hope in cancer therapeutics.

Silk Nanofiber Carriers for Both Hydrophilic and Hydrophobic Drugs to Achieve Improved Combination Chemotherapy.

Combination chemotherapy is considered an effective strategy to inhibit tumor growth. Here, beta-sheet-rich silk nanofibers are co-loaded with hydrophilic doxorubicin (DOX) and hydrophobic paclitaxel (PTX) through a sequential physical blending-centrifugation-blending process. The ratio and amount of DOX and PTX on the nanofibers are regulated independently to optimize cooperative interaction. Both PTX and DOX are immobilized on the same nanofibers to avoid burst release problems. Besides the water-insoluble PTX, more than half of the DOX remained fixed on the nanofibers for more than 28 days, which facilitated the co-internalization of both DOX and PTX by tumor cells in vitro. Changing the ratio of co-loaded DOX and PTX achieved optimal combination therapy in vitro. The DOX-PTX co-loaded nanofibers are assembled into injectable hydrogels to facilitate in situ injection around tumor tissues in vivo. Long-term inhibition is achieved for tumors treated with DOX-PTX co-loaded hydrogels, superior to those treated with free DOX and PTX, and hydrogels loaded with only DOX or PTX. Considering the mild and controllable physical loading process and superior loading capacity for both hydrophilic and hydrophobic ingredients, these injectable silk nanofiber hydrogels are promising carriers to deliver multiple drug types simultaneously in situ, enhancing combination chemotherapies towards clinical applications.

A bibliometric and knowledge-map analysis of bispecific antibodies in cancer immunotherapy from 2000 to 2023

BackgroundBispecific antibody (BsAb)-based cancer immunotherapy has provided new avenues for the treatment of various malignancies. The approval of Blinatumomab has encouraged further investigation into these treatments, and a series of preclinical and clinical trials have been conducted, together with the publication of numerous articles. Here, the knowledge structure of BsAb-based cancer immunotherapy is summarized using bibliometric analysis to provide in-depth insight into current research trends and foci. MethodsThe studies included in the bibliometric analysis of BsAbs in cancer immunotherapy were retrieved from the online Web of Science Core Collection (WOSCC) database on April 16th, 2023. Visualization analysis was performed with the help of CtieSpace (version 6.2.2.msi [64-bit]), VOSviewer (version 1.6.19), R (version 4.2.1), and the Bibliometric analysis platform (R-based online data processing tool). ResultsA total of 1750 papers were identified. Analysis of annual publications and total citations indicated that publications have increased steadily over the past few decades. The USA, followed by Germany, had largest number of publications, making significant contributions to the field. The Memorial Sloan Kettering Cancer Center received the highest number of citations (n = 3769). However, its collaboration and cooperation with different institutions require further strengthening. MAbs and Clinical Cancer Research published the most papers, while Blood and Cancer Research were the most commonly co-cited journals. DM Goldenberg from the USA published the most articles with the highest H-index (34), and the most co-cited author (2137 citations) was PA Baeuerle; both these authors have distinguished achievements in this field. Analysis of co-cited references and keywords showed that the hotspots and research focus on the use of BsAbs for solid tumors have increased rapidly while the application of BsAb immunotherapy in hematologic malignancies has expanded significantly. The hot topics in the field included cytokine release syndrome, the efficacy and safety of BsAbs, resistance mechanisms, and the exploration and optimization of combination therapies. ConclusionCancer immunotherapies based on BsAbs are a hot topic in research. Current studies focus on the construction and optimization of BsAb structure, as well as their combination with other treatment modalities to improve their efficacy and overcome resistance. Furthermore, it is expected that the ongoing investigation of BsAb-based immunotherapy for solid tumors will bear fruit with significant clinical application prospects in the near future.

Androgen receptor, PARP signaling, and tumor microenvironment: the 'perfect triad' in prostate cancer?

Aberrations in the homologous recombination repair (HRR) pathway in prostate cancer (PCa) provide a unique opportunity to develop therapeutic strategies that take advantage of the reduced tumor ability to repair DNA damage. Poly-ADP-ribose polymerase (PARP) inhibitors (PARPi) have been shown to prolong the survival of PCa patients with HRR defects, particularly in those with Breast Cancer type 1 susceptibility protein/Breast Cancer type 2 susceptibility protein alterations. To expand the benefit of PARPi to patients without detectable HRR alterations, multiple preclinical and clinical studies are addressing potential synergies between PARPi and androgen receptor signaling inhibitors, and these strategies are also being evaluated in combination with other drugs such as immune checkpoint inhibitors. However, the effectiveness of these combining therapies could be hindered by multiple mechanisms of resistance, including also the role played by the immunosuppressive tumor microenvironment. In this review, we summarize the use of PARPi in PCa and the potential synergies with different molecular pathways. However, numerous unanswered questions remain, including the identification of the patient population that could benefit most from PARPi, determining whether to use PARPi as monotherapy or in combination, and finding the optimal timing of PARPi, expanding the use of genomic tests, and optimizing combination therapies.

Current status and challenges of AML treatment with FLT3 inhibitors

FLT3 mutation is one of the most frequent genetic mutations in AML, identified in approximately 30% of patients, and FLT3-ITD mutation is considered a poor prognostic factor. Based on these molecular and clinical backgrounds, FLT3 mutations are considered promising therapeutic targets in AML, and intensive development of targeted therapeutics has been ongoing for more than two decades. Recently, combination of FLT3 inhibitors with intensive chemotherapy for untreated AML patients with FLT3 mutations and FLT3 inhibitor monotherapy for relapsed/refractory patients have been approved. In Japan, the combination of quizartinib and intensive chemotherapy for untreated FLT3-ITD-positive AML was approved in 2023. Clinical use of FLT3 inhibitors shows strong promise for improving the clinical outcomes of these AML patients with an extremely poor prognosis. Meanwhile, various resistance mechanisms to FLT3 inhibitors have been identified, including the emergence of resistance-associated mutations, and attenuated inhibitory effects of FLT3 inhibitors involving the bone marrow microenvironment surrounding AML cells. Thus, future efforts should aim to optimize combination therapy based on the characteristics of each FLT3 inhibitor, develop biomarkers that could inform treatment selection, and to better understand these resistance mechanisms and develop methods for overcoming them.

Immunotherapy for head and neck cancer: where do we go from here?

Tweetable abstract Immunotherapy for head and neck cancer shows promising new directions - and challenges ahead. What can we learn from recent trials to improve patient selection and optimize combination therapy?

Long-Term Clinical Outcomes of Optimizing Combination Therapy for Primary Pulmonary Mucosa-Associated Lymphoid Tissue Lymphoma: A Retrospective Study

Introduction: Pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma progresses with advancing disease stage. However, no standard treatment approach has been established. This single-center retrospective study evaluated clinical and radiological characteristics, treatment modalities, and long-term prognosis of pulmonary MALT lymphoma. Methods: The study included 42 patients diagnosed with pulmonary MALT lymphoma between October 2004 and July 2019. Primary therapeutic modalities were determined using modified Ann Arbor staging. Therapeutic response was evaluated via computed tomography and laboratory analyses every 6 months for 5 years. Radiological findings were categorized based on the Lugano classification as complete response (CR), partial response, stable disease (SD), or progressive disease. Results: Initial treatment included observation (n = 2), surgical resection (n = 6), or systemic chemotherapy (n = 34). Patients treated surgically had localized disease and achieved initial and long-term CR. Of the 34 patients who underwent chemotherapy, 30 achieved CR, 2 achieved SD, and 2 died. Overall and progression-free survival (PFS) rates were 93.9% and 54.3%, respectively. Multivariate analysis indicated that PFS was lower in patients with modified Ann Arbor stage III-IV lymphoma and those who did not achieve CR. Conclusions: Optimized treatment based on anatomical location, pulmonary function, and disease stage can improve long-term survival in patients with pulmonary MALT lymphoma.

Efficacy and Safety Analysis of Combination Therapy Based on Liposomal Mitoxantrone (Lipo-MIT) in Relapsed/Refractory NK/T-Cell Lymphoma

Background: Currently, there is no standard treatment for relapsed/refractory NK/T-cell lymphoma (NKTCL), which is characterized by highly aggressive and poor prognosis. New drugs are urgently needed to improve the therapeutic effect. Liposomal mitoxantrone (Lipo-MIT) is approved in China for the treatment of relapsed or refractory peripheral T-cell lymphoma patients who have received at least one line standard therapy previously. Phase II study data showed that the objective response rate (ORR) of patients after monotherapy was 41.7% and the complete response rate (CR) was 23.1%. Progression-free survival (PFS) was 8.5 months. Lipo-MIT showed excellent anti-tumor effect in patients with NKTCL subtype, with an ORR of 42.9%, which broke the limitation of natural resistance of NKTCL to anthracyclines. To further improve the efficacy, we tried a combination therapy based on Lipo-MIT in patients with relapsed/refractory NKTCL. Herein we will report its efficacy and safety. Methods: Nine patients with relapsed/refractory NKTCL were enrolled in this study, all of whom had previously received pegaspargase-based combination chemotherapy. The salvage treatment was a combination regimen based on Lipo-MIT. The efficacy was evaluated after every 2 cycles using PET-CT or MRI scan, and hematological and non-hematological adverse events were collected after treatment. Progression-free survival (PFS) was defined as the time from initiation of Lipo-MIT to disease progression, recurrence, death, or last follow-up. Overall survival time (OS) was defined as the time from initiation of Lipo-MIT to death from all causes or the last follow-up. Results: The median age of the nine patients was 53 years old (17-67 years old), and the male-female ratio was 7:2. Eight patients had stage IV NKTCL, one was stage II NKTCL, and all patients had an NRI score of ≥3. The median number of previous treatment lines was 2 (1-4). Three patients had recurrent NKTCL, and six patients had refractory disease to previous treatments, among whom two patients had concurrent hemophagocytic syndrome. The salvage treatment regimens were as follows: Lipo-MIT + pegaspargase + dexamethasone (N=3); Lipo-MIT + pegaspargase + dexamethasone +PD1 monoclonal antibody (N=2); Lipo-MIT +PD1 monoclonal antibody + dexamethasone (N=2); Lipo-MIT + etoposide + pegaspargase + dexamethasone (N=2). Efficacy was evaluable in all patients and the median number of treatment cycles was 3 (2-6). The best response rates were as follows: complete response in 3 (33.3%) patients, partial response in 4 (44.4%) patients, stable disease in 1 (11.1%) patient, and progressive disease in 1 (11.1%) patient. At a median follow-up of 4 months (2-13 months), 6 patients died, including 5 from disease progression and 1 from pegaspargase -associated acute pancreatitis, with a median PFS of 5 months and a median OS of 7 months. One patient underwent allogeneic hematopoietic stem cell transplantation after achieving a complete response and has been disease-free for more than 13 months now. The main adverse reactions of Lipo-MIT combination regimen were grade 3 or more bone marrow suppression (N=7), skin cyanosis (N=4), liver insufficiency (N=4), coagulation dysfunction (N=4), acute pancreatitis (N=1). The median recovery time from myelosuppression was 17 days (6-35 days). There was no correlation between skin cyanosis and efficacy. Conclusion: Combination therapy based on Lipo-MIT has a high remission rate for relapsed/refractory NKTCL, but the duration of remission needs to be further extended, and subsequent allogeneic hematopoietic stem cell transplantation may prolong survival. Lipo-MIT has obvious myelosuppression toxicity, and active supportive therapy should be given when combined with other cytotoxic drugs. In the future, it is worthwhile to conduct prospective clinical trials to explore the optimal combination therapy based on Lipo-MIT in relapsed/refractory NKTCL.

Extending the boundaries of cancer therapeutic complexity with literature text mining

Drug combination therapy is a main pillar of cancer therapy. As the number of possible drug candidates for combinations grows, the development of optimal high complexity combination therapies (involving 4 or more drugs per treatment) such as RCHOP-I and FOLFIRINOX becomes increasingly challenging due to combinatorial explosion. In this paper, we propose a text mining (TM) based tool and workflow for rapid generation of high complexity combination treatments (HCCT) in order to extend the boundaries of complexity in cancer treatments. Our primary objectives were: (1) Characterize the existing limitations in combination therapy; (2) Develop and introduce the Plan Builder (PB) to utilize existing literature for drug combination effectively; (3) Evaluate PB's potential in accelerating the development of HCCT plans. Our results demonstrate that researchers and experts using PB are able to create HCCT plans at much greater speed and quality compared to conventional methods. By releasing PB, we hope to enable more researchers to engage with HCCT planning and demonstrate its clinical efficacy.

Multifunctional Mesoporous Polydopamine‐Based Systematic Delivery of STING Agonist for Enhanced Synergistic Photothermal‐Immunotherapy

AbstractThe therapeutic application of STING agonists in various malignancies has been limited by factors such as the inability of systemic administration and the immunosuppressive tumor microenvironment. Herein, this work reports a mesoporous polydopamine‐based multifunctional nanoplatform loaded with STING agonist MSA‐2 and chelated with Mn2+ for synergistic photothermal and STING activation‐based immunotherapy. The nanoplatform effectively delivers MSA‐2 to the tumor site and intelligently releases its contents through acid degradation, facilitated by the photothermal effect. Additionally, the thermal ablation of tumor tissue can induce immunogenic cell death, which helps alleviate the immunosuppressive tumor microenvironment, thereby enhancing the efficacy of MSA‐2. Furthermore, Mn2+ works as a dual‐acting STING sensitizer and MRI contrast agent which not only boosts the immune response but also allows real‐time MRI tracking of the nanoplatform. This strategy is proved highly efficacious both in impeding primary/metastatic tumor and in eliciting a robust tumor‐specific immune response. Collectively, an effective multifunctional nanoplatform for the systemic delivery of STING agonist which synergized photothermal therapy and STING pathway activation‐mediated immunotherapy is highlighted here to provide new ideas and strategies for optimizing combination therapy for cancer treatment.

Optimal combination therapy for metastatic hormone-sensitive prostate cancer: new evidence, challenges and unanswered questions.

To evaluate the evidence supporting treatment intensification in mHSPC, with a focus on possible indications for treatment in each clinical setting. There is a growing armamentarium of treatment options for patients with metastatic hormone-sensitive prostate cancer (mHSPC). These include combinations of treatments such as androgen deprivation therapy (ADT), docetaxel, and new antiandrogenic therapies. Treatment intensification with chemotherapy or newer hormonal agents may improve patient's oncologic outcomes, but it can also come with additional toxicities and costs. Therefore, we need to take into account individual patient factors and preferences when deciding on the optimal combination therapy. Additionally, ongoing research is needed to identify biomarkers and new image techniques that can predict response to treatment and identify the best candidate for each treatment. Challenges and unanswered questions regarding treatment intensification and de-intensification are still present. Further studies are still needed to identify which patients would benefit most from this approach to improve quality of life without compromising overall survival outcomes.

Using quantitative systems pharmacology modeling to optimize combination therapy of anti-PD-L1 checkpoint inhibitor and T cell engager.

Although immune checkpoint blockade therapies have shown evidence of clinical effectiveness in many types of cancer, the outcome of clinical trials shows that very few patients with colorectal cancer benefit from treatments with checkpoint inhibitors. Bispecific T cell engagers (TCEs) are gaining popularity because they can improve patients' immunological responses by promoting T cell activation. The possibility of combining TCEs with checkpoint inhibitors to increase tumor response and patient survival has been highlighted by preclinical and clinical outcomes. However, identifying predictive biomarkers and optimal dose regimens for individual patients to benefit from combination therapy remains one of the main challenges. In this article, we describe a modular quantitative systems pharmacology (QSP) platform for immuno-oncology that includes specific processes of immune-cancer cell interactions and was created based on published data on colorectal cancer. We generated a virtual patient cohort with the model to conduct in silico virtual clinical trials for combination therapy of a PD-L1 checkpoint inhibitor (atezolizumab) and a bispecific T cell engager (cibisatamab). Using the model calibrated against the clinical trials, we conducted several virtual clinical trials to compare various doses and schedules of administration for two drugs with the goal of therapy optimization. Moreover, we quantified the score of drug synergy for these two drugs to further study the role of the combination therapy.

Novel Synergies and Isolate Specificities in the Drug Interaction Landscape of Mycobacterium abscessus.

Mycobacterium abscessus infections are difficult to treat and are often considered untreatable without tissue resection. Due to the intrinsic drug-resistant nature of the bacteria, combination therapy of three or more antibiotics is recommended. A major challenge in treating M. abscessus infections is the absence of a universal combination therapy with satisfying clinical success rates, leaving clinicians to treat infections using antibiotics lacking efficacy data. We systematically measured drug combinations in M. abscessus to establish a resource of drug interaction data and identify patterns of synergy to help design optimized combination therapies. We measured 191 pairwise drug combination effects among 22 antibacterials and identified 71 synergistic pairs, 54 antagonistic pairs, and 66 potentiator-antibiotic pairs. We found that commonly used drug combinations in the clinic, such as azithromycin and amikacin, are antagonistic in the lab reference strain ATCC 19977, whereas novel combinations, such as azithromycin and rifampicin, are synergistic. Another challenge in developing universally effective multidrug therapies for M. abscessus is the significant variation in drug response between isolates. We measured drug interactions in a focused set of 36 drug pairs across a small panel of clinical isolates with rough and smooth morphotypes. We observed strain-dependent drug interactions that cannot be predicted from single-drug susceptibility profiles or known drug mechanisms of action. Our study demonstrates the immense potential to identify synergistic drug combinations in the vast drug combination space and emphasizes the importance of strain-specific combination measurements for designing improved therapeutic interventions.

Combined expression of HIF1α, VEGF and HER2 predicts metastasis, relapse and response to combination chemotherapy in colorectal cancer patients

Addressing a single target is the frequent development of drug resistance followed by cancer relapse and treatment failure. Therefore, assessment of simultaneous expression of target molecules is essential to choose the optimal combination therapy for each colorectal cancer patient.This study aims to evaluate the immunohistochemical expression of HIF1α, HER2 and VEGF and to clarify their clinical significance as prognostic factors and predictive markers of FOLFOX (combination chemotherapy inclusive of Leucovorin calcium, Fluorouracil and Oxaliplatin response).Marker expression was retrospectively evaluated by immunohistochemistry in 111 patients with colorectal adenocarcinomas from south Tunisia, followed by statistical analysis.The immunohistochemical staining revealed that 45 %, 80.2 %, 86.5 % and 25.5 % of specimen were positive for nuclear, cytoplasmic HIF1α expression, VEGF and HER2 respectively. Nuclear HIF1α and VEGF were associated with worst prognosis while cytoplasmic HIF1α and HER2 were correlated with favourable prognosis. Multivariate analysis confirms the association between nuclear HIF1α, distant metastasis, relapse, FOLFOX response and 5 years overall survival. HIF1α positivity and HER2 negativity were significantly associated to short survival. Combined immunoprofiles HIF1α+/VEGF+, HIF1α+/HER2-, HIF1α+/VEGF+/HER2- were associated to distant metastasis, cancer relapse and short survival. Interestingly, our findings confirmed that patients bearing a HIF1α positive tumor were significantly more resistant to FOLFOX compared to negative ones (p = 0.002, p ≤ 0.001). Positive expression of HIF1α and VEGF, or decreased expression of HER2 was each associated with poor prognosis and short overall survival. In summary, we found that expression of nuclear HIF1α, alone or combined with VEGF and HER2 serves as a predictive marker of poor prognosis and FOLFOX response in colorectal cancer from south Tunisia.

A Convex Formulation for Robust Control of Bilinear Positive Systems With Evolutionary Dynamics

In this article, optimal control of bilinear positive systems with uncertain evolutionary dynamics is studied. The first objective is to determine optimal control signals such that the effect of the disturbance signals on the outputs of the nominal dynamics is minimized in terms of the <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$\mathcal{H}_2$</tex-math> </inline-formula> norm performance index. Properties of the positive systems, Metzler matrices, and the exploitable structure of the problem are utilized to show that the underlying problem is representable as a standard convex optimization problem. Next, the optimal strategy is examined in the presence of polytopic uncertainties. In this case, the optimization problem is a semi-infinite min-max problem. It is shown that under some assumptions, the underlying problem is equivalent to a finite min-max problem, i.e., it suffices to check only the vertices of the polytopic set for <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$\mathcal{H}_2$</tex-math> </inline-formula> norm minimization. The proposed approach for polytopic bilinear positive systems is non-iterative, does not involve parameter tuning or nonsmooth optimization algorithms, and can be solved using off-the-shelf solvers. The effectiveness of the proposed approach is investigated for the optimal combination therapy of human immunodeficiency virus (HIV).

Abstract SY32-03: Overcoming PARP inhibitor resistance through rational combinations in the clinic

Abstract Genomic instability is a key hallmark of cancer that arises owing to defects in the DNA damage response (DDR) and/or increased replication stress. The therapeutic landscape of antitumor agents targeting the DDR has rapidly expanded to include inhibitors of key mediators of DNA repair and replication beyond PARP, such as ATR and WEE1. Dr Yap will cover the latest advances in biomarker-driven synthetic lethal combination treatment strategies for different cancers. He will discuss efforts to optimize combination therapies that are ongoing across a range of cancers, involving the development of predictive biomarkers of response, assessment of the mechanisms underlying resistance, and the evaluation of rational, tolerable combinations with novel molecularly targeted agents, immune-checkpoint inhibitors and antibody drug conjugates. Citation Format: Timothy A. Yap. Overcoming PARP inhibitor resistance through rational combinations in the clinic. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr SY32-03.

Abstract 5485: Clinical evaluation of a functional combinatorial precision medicine platform reveals combination-specific sub-populations in t-cell lymphoma

Abstract T-cell lymphoma (TCL) is a heterogenous subgroup of non-Hodgkin’s lymphoma with poor prognosis. Approved targeted monotherapies have seen limited success due to lack of effective combinations or identification of sensitive patient populations. Hence, there is a need to develop alternative strategies to identify effective combinations for individual patients and specific TCL sub-populations. We interrogated the potential for an ex vivo combinatorial drug sensitivity platform, Quadratic Phenotypic Optimization Platform (QPOP), in a clinical study for relapsed/refractory Non-Hodgkin Lymphoma (RR-NHL) to identify effective subtype-specific combinations through a functional combinatorial precision medicine approach. We analyzed 37 primary samples from patients with RR-NHL of both T- and NK-cell origin in Singapore, with disease amenable to biopsy or blood/marrow aspiration. Single cell suspensions from tumor samples were treated with a panel of 12 drugs with known preclinical or clinical efficacy against TCL. Post-drug treatment cell viability was used as a phenotypic input for QPOP analysis, which maps experimental data points to a second-order quadratic function to predict cell killing efficacies for all possible permutations of drug combinations. Romidepsin-based combinations appeared among the top ranked QPOP-derived 2-drug combinations with predicted output cutoff &amp;lt; 0.55 in 91.8% of samples treated with similar QPOP drug panel. Among these combinations, combinations with copanlisib, ifosfamide and venetoclax were the most frequently occurring doublet, appearing in 24, 14 and 8 samples, respectively. A total of 10 patients received QPOP-derived romidepsin-based combinations at physicians’ discretion. We noted outcomes of stable disease or better in 7/10 (70%) patients, with clinical benefit seen in 2 complete responses and 2 partial responses (40%). Thus, romidepsin-based combinations showed improved outcomes for TCL patients compared to the prior reported overall response rate of 25% that led to romidepsin’s approval as monotherapy. This study showed the clinical utility of QPOP in identifying combination therapy-specific sub-populations in TCL. Targeted agents, such as romidepsin, copanlisib and venetoclax, that have previously been explored as single agents in TCL were predicted by QPOP to be more effective in the proper combination for the proper patient. This study demonstrates that functional combinatorial precision medicine platforms, such as QPOP, may improve clinical outcomes through identification of more appropriate combination therapies. This work, as well as additional studies in other cancer types, provide evidence towards the need for optimal combination therapy design and the potential of functional precision medicine to improve precision and personalized cancer treatment. Citation Format: Edward Kai-Hua Chow, Masturah Rashid, Sanjay Prasad De Mel, Jasmine Goh, Anand Jeyasekharan. Clinical evaluation of a functional combinatorial precision medicine platform reveals combination-specific sub-populations in t-cell lymphoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5485.

Additive Therapy of Plasmodium berghei-Induced Experimental Cerebral Malaria via Dihydroartemisinin Combined with Rapamycin and Atorvastatin.

Cerebral malaria (CM), caused by Plasmodium falciparum, is the primary cause of death from severe malaria. Even after immediate parenteral therapy with antimalarial drugs, the mortality rate remains 15 to 25%. Currently, no effective therapeutic agents are available for the radical treatment of CM. Thus, further in-depth explorations of adjuvant therapies in combination with antimalarial drugs are urgently needed. The experimental cerebral malaria (ECM) model was established by infecting C57BL/6 mice with Plasmodium berghei ANKA. Subsequently, infected mice were continuously treated with dihydroartemisinin (DHA) in combination with rapamycin (RAP) and atorvastatin (AVA) for 5 days at different time points, including day 0, day 3, and day 6 postinfection (p.i.). Treatment efficacy was evaluated by comparing behavioral scores, body weight, parasitemia, survival rate, blood-brain barrier (BBB) integrity, and histopathology. The optimal combination therapy of DHA, RAP, and AVA on day 3 p.i. was selected for ECM. This strategy significantly improved survival rate, reduced parasitemia, improved the rapid murine coma and behavioral scale scores and permeability of the BBB, attenuated cerebrovascular and hepatic central venous obstruction and hemozoin deposition in the liver, and decreased the red pulp area of the spleen, which effectively ameliorated neurological damage in ECM. It also improved histopathology and neurological damage caused by ECM. In this study, the optimal therapeutic strategy for ECM was selected, which is expected to be a potential therapy for human CM. IMPORTANCE Although artemisinin-based combination therapies (ACTs) have greatly improved the clinical outcome of cerebral malaria (CM) as a fatal disease that can permanently disable a significant proportion of children even if they survive, new treatment options are needed as Plasmodium falciparum develops resistance to antimalarial drugs. Recent reports suggest that basal treatment with artemisinin derivatives often fails to protect against cell death, neurological damage, and cognitive deficits. In this study, the combination of dihydroartemisinin with rapamycin and atorvastatin improved the current antimalarial outcomes by overcoming the limitations of current antimalarials for CM morbidity and neurological sequelae. This combination offers a new adjunctive treatment for the clinical treatment of human CM in susceptible populations, including children under 5 years old and pregnant women.

A pipeline for testing drug mechanism of action and combination therapies: From microarray data to simulations via Linear-In-Flux-Expressions: Testing four-drug combinations for tuberculosis treatment

Computational methods are becoming commonly used in many areas of medical research. Recently, the modeling of biological mechanisms associated with disease pathophysiology have benefited from approaches such as Quantitative Systems Pharmacology (briefly QSP) and Physiologically Based Pharmacokinetics (briefly PBPK). These methodologies show the potential to enhance, if not substitute animal models. The main reasons for this success are the high accuracy and low cost.Solid mathematical foundations of such methods, such as compartmental systems and flux balance analysis, provide a good base on which to build computational tools. However, there are many choices to be made in model design, that will have a large impact on how these methods perform as we scale up the network or perturb the system to uncover the mechanisms of action of new compounds or therapy combinations.A computational pipeline is presented here that starts with available-omic data and utilizes advanced mathematical simulations to inform the modeling of a biochemical system. Specific attention is devoted to creating a modular workflow, including the mathematical rigorous tools to represent complex chemical reactions, and modeling drug action in terms of its impact on multiple pathways. An application to optimizing combination therapy for tuberculosis shows the potential of the approach.

In Vitro Drug Repurposing: Focus on Vasodilators.

Drug repurposing aims to identify new therapeutic uses for drugs that have already been approved for other conditions. This approach can save time and resources compared to traditional drug development, as the safety and efficacy of the repurposed drug have already been established. In the context of cancer, drug repurposing can lead to the discovery of new treatments that can target specific cancer cell lines and improve patient outcomes. Vasodilators are a class of drugs that have been shown to have the potential to influence various types of cancer. These medications work by relaxing the smooth muscle of blood vessels, increasing blood flow to tumors, and improving the delivery of chemotherapy drugs. Additionally, vasodilators have been found to have antiproliferative and proapoptotic effects on cancer cells, making them a promising target for drug repurposing. Research on vasodilators for cancer treatment has already shown promising results in preclinical and clinical studies. However, additionally research is needed to fully understand the mechanisms of action of vasodilators in cancer and determine the optimal dosing and combination therapy for patients. In this review, we aim to explore the molecular mechanisms of action of vasodilators in cancer cell lines and the current state of research on their repurposing as a treatment option. With the goal of minimizing the effort and resources required for traditional drug development, we hope to shed light on the potential of vasodilators as a viable therapeutic strategy for cancer patients.