Drug Scheduling Research Articles

Abstract IA006: Progress, pitfalls and promise: the journey to effective and well tolerated DNA damage response inhibitor combinations in the clinic

A mounting body of evidence now indicates that poly(ADP-ribose) polymerase (PARP) inhibitors have the potential to be used as a foundation for both monotherapy and combination strategies across a wide spectrum of molecular backgrounds and tumor types. There are multiple promising combination therapeutic strategies, such as those with other DNA damage response (DDR) inhibitors such as ATR inhibitors, immune checkpoint inhibitors, and non-DDR-targeted agents that induce "chemical BRCAness". Despite promising efficacy data, several of the combinations have been hampered by supra-additive toxicities, restricting the combination of full monotherapy doses and schedules of component drugs. I will discuss the progress, pitfalls and promise of different classes of DNA damage response (DDR) inhibitor combinations in the clinic, and discuss potential clinical strategies to develop effective and well tolerated combinations to target PARP inhibitor resistance and to widen the application of DDR agents beyond approved indications Citation Format: Timothy A. Progress, pitfalls and promise: the journey to effective and well tolerated DNA damage response inhibitor combinations in the clinic. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA006

Progresses and Pitfalls of Epigenetics in Solid Tumors Clinical Trials.

Epigenetic dysregulation has long been recognized as a significant contributor to tumorigenesis and tumor maintenance, impacting all recognized cancer hallmarks. Although some epigenetic drugs have received regulatory approval for certain hematological malignancies, their efficacy in treating solid tumors has so far been largely disappointing. However, recent advancements in developing new compounds and a deeper understanding of cancer biology have led to success in specific solid tumor subtypes through precision medicine approaches. Moreover, epigenetic drugs may play a crucial role in synergizing with other anticancer treatments, enhancing the sensitivity of cancer cells to various anticancer therapies, including chemotherapy, radiation therapy, hormone therapy, targeted therapy, and immunotherapy. In this review, we critically evaluate the evolution of epigenetic drugs, tracing their development from initial use as monotherapies to their current application in combination therapies. We explore the preclinical rationale, completed clinical studies, and ongoing clinical trials. Finally, we discuss trial design strategies and drug scheduling to optimize the development of possible combination therapies.

Growth of Renal Cancer Cell Lines Is Strongly Inhibited by Synergistic Activity of Low-Dosed Amygdalin and Sulforaphane.

Background: Plant derived isolated compounds or extracts enjoy great popularity among cancer patients, although knowledge about their mode of action is unclear. The present study investigated whether the combination of two herbal drugs, the cyanogenic diglucoside amygdalin and the isothiocyanate sulforaphane (SFN), influences growth and proliferation of renal cell carcinoma (RCC) cell lines. Methods: A498, Caki-1, and KTCTL-26 cells were exposed to low-dosed amygdalin (1 or 5 mg/mL), or SFN (5 µM) or to combined SFN-amygdalin. Tumor growth and proliferation were analyzed by MTT, BrdU incorporation, and clone formation assays. Cell cycle phases and cell cycle-regulating proteins were analyzed by flow cytometry and Western blotting, respectively. The effectiveness of the amygdalin-SFN combination was determined using the Bliss independence model. Results: 1 mg/mL amygdalin or 5 µM SFN, given separately, did not suppress RCC cell growth, and 5 mg/mL amygdalin only slightly diminished A498 (but not Caki-1 and KTCTL-26) cell growth. However, already 1 mg/mL amygdalin potently inhibited growth of all tumor cell lines when combined with SFN. Accordingly, 1 mg/mL amygdalin suppressed BrdU incorporation only when given together with SFN. Clonogenic growth was also drastically reduced by the drug combination, whereas only minor effects were seen under single drug treatment. Superior efficacy of co-treatment, compared to monodrug exposure, was also seen for cell cycling, with an enhanced G0/G1 and diminished G2/M phase in A498 cells. Cell cycle regulating proteins were altered differently, depending on the applied drug schedule (single versus dual application) and the RCC cell line, excepting phosphorylated Akt which was considerably diminished in all three cell lines with maximum effects induced by the drug combination. The Bliss independence analysis verified synergistic interactions between amygdalin and SFN. Conclusions: These results point to synergistic effects of amygdalin and SFN on RCC cell growth and clone formation and Akt might be a relevant target protein. The combined use of low-dosed amygdalin and SFN could, therefore, be beneficial as a complementary option to treat RCC. To evaluate clinical feasibility, the in vitro protocol must be applied to an in vivo model.

Base editing screens define the genetic landscape of cancer drug resistance mechanisms

Drug resistance is a principal limitation to the long-term efficacy of cancer therapies. Cancer genome sequencing can retrospectively delineate the genetic basis of drug resistance, but this requires large numbers of post-treatment samples to nominate causal variants. Here we prospectively identify genetic mechanisms of resistance to ten oncology drugs from CRISPR base editing mutagenesis screens in four cancer cell lines using a guide RNA library predicted to install 32,476 variants in 11 cancer genes. We identify four functional classes of protein variants modulating drug sensitivity and use single-cell transcriptomics to reveal how these variants operate through distinct mechanisms, including eliciting a drug-addicted cell state. We identify variants that can be targeted with alternative inhibitors to overcome resistance and functionally validate an epidermal growth factor receptor (EGFR) variant that sensitizes lung cancer cells to EGFR inhibitors. Our variant-to-function map has implications for patient stratification, therapy combinations and drug scheduling in cancer treatment.

Survey of community pharmacists' opinions on drug scheduling in Ontario and Québec.

Over the past decade, Canada has witnessed a shift of several drugs from prescription-only to behind-the-counter (BTC) and over-the-counter (OTC) status. This work examined community pharmacists' agreement with the current scheduling of agents used in the management of allergic rhinitis, heartburn, and vulvovaginitis. From September to October 2022, an online survey was administered to pharmacists practicing in in Ontario and Québec. The survey aimed to gather insights into their preferred scheduling for 15 medicines commonly used to manage the three selected conditions. Pharmacists were asked whether they agreed with the current scheduling status of each and, if not, how they feel it should be scheduled. 715 pharmacists completed the survey, 462 from Ontario and 253 from Québec. Most were staff pharmacists working 30 or more hours per week, having been a pharmacist for 1-10 years. Ontario pharmacists expressed a preference for scheduling change for five drugs (four prescription [terconazole for intravaginal use, famotidine, rupatadine, mometasone nasal spray] and one unscheduled [ranitidine 75 mg]), while Québec pharmacists expressed preference for scheduling change for three prescription drugs (terconazole for intravaginal use, famotidine, rupatadine). As pharmacy practice continues to evolve, pharmacists' comfort with initiating previously prescription-only therapy independently or assisting patients with self-selection may similarly evolve. Of the five drugs identified as having a discrepancy between current status and pharmacist preference, four are prescription and may be candidates to consider for prescription to OTC switch. Pharmacists in Ontario and Québec have expressed preference for most products used in the treatment of allergic rhinitis, heartburn, and vulvovaginitis to be categorised as Schedule II (BTC) or Schedule III (OTC) available only in pharmacies.

Neuropsychiatric manifestations of Wilson’s disease – A therapeutic challenge

Abstract: Wilson’s disease (WD) occurs due to abnormal copper metabolism and often presents with various neurological, cognitive, and psychiatric symptoms. Variable symptoms and a high propensity for medication-related adverse effects frequently make their management difficult. Here, we discussed two cases of WD presented to psychiatric OPD with variable neuropsychiatric symptoms managed conservatively but frequently complicated by newer symptoms, and medication-related side effects, which lead to multiple consultations and frequent changes in drug schedule. Therefore, we found it a great therapeutic challenge, and more discussion and research are warranted for such a condition.

Portable Medication Reminder System for Elderly and Alzheimer's Patients

As healthcare demands rise and the senior population grows, innovative results are essential for cases with habitual ails and memory-related conditions like Alzheimer's. Introduces a movable drug memorial System designed for hospitals, old age homes, and independent elderly citizens. The system, erected around an Arduino UNO microcontroller, integrates an IR detector, buzzer, TV display, RTC module, keypad, LED, and GSM module, working together to give timely drug monuments. In hospitals, it integrates into patient care routines, driving visual and audile monuments for nursing staff to insure timely drug delivery. This integration helps drug crimes and ensures that cases are cleaved to their prescribed treatment plans. Old age homes profit from the stonerfriendly device, allowing residents to manage their drug schedules via the TV display and keypad. The system's simplicity and trust ability can significantly ameliorate the quality of life for senior residents. For independent seniors, the movable system provides monuments through the TV display and buzzer, with the GSM module transferring SMS cautions to family members or caregivers if boluses are missed. This point is particularly precious for those who live alone, offering peace of mind to both the seniors and their families. Alzheimer's cases, floundering with memory loss and drug adherence, gain significantly from this system. The combination of visual and audile monuments, along with the straightforward keypad and TV display, offers an effective tool for managing their drug needs. By icing timely drug input, alleviates the progression of symptoms and enhances the overall well-being of Alzheimer's cases.

A Comprehensive Analysis of Medication Errors on Antimicrobials in a Tertiary Care Hospital of Northern India

Background: Medication errors, resulting from incomplete understanding, pose significant risks to patient safety. Antimicrobial medication error is a global concern further exacerbated by underreporting. This study aims to determine the prevalence of antimicrobial medication errors at a tertiary care medical facility. Methodology: A retrospective study was conducted over six months. Antimicrobial medication errors were analyzed and categorized as prescription, transcription, indenting, dispensing, and administration errors. A total of 208 antimicrobial medication errors were analyzed using the National Coordinating Council for Medication Error Reporting and Prevention (NCCMERP) risk index. Results: Among 6,439 medication charts assessed, 558 (9%) medication errors were identified, with antimicrobial errors accounting for 208 (37.2%). Prescription errors were the most prevalent (61%), followed by transcription errors (16%) and administration errors (11%). Dispensing, indenting, and documentation errors occurred at rates of 8%, 2%, and 2%, respectively. The primary causes of errors were incorrect doses (47.2%) and frequencies (30%). Approximately 55.3% of antimicrobial medication errors were classified as Category C according to the NCCMERP risk assessment. Conclusion: Prescription errors represent the majority of antimicrobial medication errors, underscoring the need for enhanced vigilance among consultant physicians during prescription writing and drug schedule checks.

A content analysis of legal policy responses to xylazine in the illicit drug supply in the United States

BackgroundXylazine is a veterinary sedative that is quickly spreading in the U.S. illicit drug supply and is increasingly associated with fatal overdoses and severe wounds. In response, xylazine has been deemed an emerging public health threat and several policy initiatives have been introduced to combat its spread and negative broad health impact. We aimed to synthesize trends in all-time U.S. policy responses to xylazine in the drug supply. MethodsIn April 2024, we systematically identified and categorized proposed and enacted policy initiatives that related to human xylazine consumption by searching LexisNexis and Thomas Reuters Westlaw legal databases. ResultsOf 58 unique policy initiatives, most were introduced in 2023 (n = 37/58, 64 %) and concentrated in Northeastern states. Penalties for xylazine possession, often tied to state drug scheduling changes, were the most common provision (n = 34/58; 59 %) and Schedule III was the most frequently proposed scheduling level (n = 17/30; 57 %). Other provisions included proposals to enhance: test strip access (n = 11/58; 19 %), public awareness and education (n = 3/58; 5 %), xylazine-specific research (n = 4/58; 7 %), and surveillance (n = 8/58; 14 %). ConclusionU.S. state and federal policy responses to xylazine grew rapidly in 2023, were most concentrated in states affected most by xylazine, and scheduling was the most commonly proposed policy approach. Research measuring policy effects should be prioritized as policies are implemented.

Treatment of Heartburn: A Survey of Ontario and Québec Community Pharmacists.

The shift of proton pump inhibitors (PPIs) from prescription to nonprescription (nonRx) status in Canada has altered pharmacist treatment options for heartburn. This report examines pharmacist approaches to therapy based on case severity; pharmacist confidence and consult duration were also explored. A 2022 online survey gathered data from Ontario and Québec pharmacists regarding their therapeutic approaches for two hypothetical heartburn cases. A total of 715 pharmacists participated, with most having 1-10 years of experience. In Ontario, common choices for the milder case included a solo histamine-2 receptor antagonist (H2RA) (21.2%), combination H2RA + antacid (29.4%), and nonRx PPI (22.3%). For the more severe case, common choices for Québec were switches to nonRx H2RA (22.1%), combination H2RA + antacid (13.4%), a nonRx PPI (24.9%), or prescription PPI (22.5%). Pharmacists often recommended switching medications or referring patients with recurring symptoms after seven days. The approaches varied significantly between cases and provinces. The Ontario pharmacists favoured a combination H2RA + antacid for the milder case, while the Québec pharmacists preferred a solo H2RA. For the more severe case, both groups often chose nonRx H2RA followed by nonRx PPI. Despite the differences, the pharmacists demonstrated confidence in managing these situations. These findings highlight potential debates regarding optimal therapeutic approaches and the impact of drug scheduling on patient care.

Antiangiogenic-immune-checkpoint inhibitor combinations: lessons from phase III clinical trials.

Antiangiogenic agents, generally antibodies or tyrosine-kinase inhibitors that target the VEGF-VEGFR pathway, are currently among the few combination partners clinically proven to improve the efficacy of immune-checkpoint inhibitors (ICIs). This benefit has been demonstrated in pivotal phase III trials across different cancer types, some with practice-changing results; however, numerous phase III trials have also had negative results. The rationale for using antiangiogenic drugs as partners for ICIs relies primarily on blocking the multiple immunosuppressive effects of VEGF and inducing several different vascular-modulating effects that can stimulate immunity, such as vascular normalization leading to increased intratumoural blood perfusion and flow, and inhibition of pro-apoptotic effects of endothelial cells on T cells, among others. Conversely, VEGF blockade can also cause changes that suppress antitumour immunity, such as increased tumour hypoxia, and reduced intratumoural ingress of co-administered ICIs. As a result, the net clinical benefits from antiangiogenic-ICI combinations will be determined by the balance between the opposing effects of VEGF signalling and its inhibition on the antitumour immune response. In this Perspective, we summarize the results from the currently completed phase III trials evaluating antiangiogenic agent-ICI combinations. We also discuss strategies to improve the efficacy of these combinations, focusing on aspects that include the deleterious functions of VEGF-VEGFR inhibition on antitumour immunity, vessel co-option as a driver of non-angiogenic tumour growth, clinical trial design, or the rationale for drug selection, dosing and scheduling.

Mathematical Model-Driven Deep Learning Enables Personalized Adaptive Therapy.

Generation of interpretable and personalized adaptive treatment schedules using a deep reinforcement framework that interacts with a virtual patient model overcomes the limitations of standardized strategies caused by heterogeneous treatment responses.

Abstract 4761: Understanding three-drug combinations: optimizing scheduling while avoiding toxicity

Abstract The promise of combination therapies in managing tumor resistance is constrained by the therapeutic window (the difference between efficacious and toxic doses). We have sought to understand the impact of dose scheduling on the emergence of resistance, using a mathematical model-based approach linking pharmacokinetics (PK) to a parsimonious evolutionary model of tumor growth incorporating the emergence of drug resistance. Here, we analyze the potential of a three-drug combination to minimize toxicity while preventing the emergence of resistance. We simulated eight tumor subpopulations representing resistance to one, two or three hypothetical drugs, using an exponential growth model with growth penalties based on drug concentrations. We used the model to simulate the effects of pairs of antagonistic, synergistic, and additive drugs on the growth of sensitive and resistant populations in a tumor. Final tumor volume and resistant population were used to compare the efficacy of various drug schedules. We assumed an overlapping neutropenia-like toxicity as the dose-limiting toxicity for the three drug combination, which we have previously shown to be proportional to the peak moving average drug concentration over 18 days. Final tumor volume and peak toxicity were used to compare the effectiveness of various dosing strategies and interaction combinations. Synchronous dosing results in the greatest drug interaction effect between any two drugs. When all interactions between the three drugs are either antagonistic or synergistic, the greatest effect is observed when all drugs are dosed simultaneously. The drugs are most toxic when all three are dosed simultaneously or nearly simultaneously. Our work shows that time sensitivity—that is, the magnitude of the changes in efficacy associated with small changes in schedule—varies with phase offset. Scheduling is most time sensitive when all drugs are dosed simultaneously or nearly simultaneously; dosing of two drugs simultaneously is less time sensitive. Three-drug combinations are an effective means of preventing complete resistance. While simultaneous dosing of two or more drugs confers the greatest efficacy, such simultaneous dosing results in greater peak toxicity because of higher simultaneous drug concentrations. A potential compromise is the simultaneous dosing of two of the three drugs, which results in an intermediate toxicity. Dosing of two drugs simultaneously is also less time sensitive, advantageous in a practical sense as it is more robust to patient dosing error. While the approach used here is based on hypothetical drug properties, it provides a framework that is readily applicable to real-world drug combinations, with the potential for practical insights to guide the framing of the Target Product Profile for three-drug combinations. Citation Format: Madison Stoddard, Lin Yuan, Debra Van Egeren, Andrew Chen, Dean Bottino, Arijit Chakravarty. Understanding three-drug combinations: optimizing scheduling while avoiding toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4761.

Abstract 4310: Impact of drug combination schedules on the evolution of tumor resistance

Abstract The emergence of drug resistance during treatment is a critical limiting factor for the long-term effectiveness of anticancer therapies. The use of drug combinations limits the emergence of resistance, thereby prolonging their therapeutic utility. The effect of a drug combination is dependent both on the concentration of the individual drugs and the extent of their interaction (synergistic, additive, or antagonistic). Thus, understanding the scheduling implications for efficacy can be valuable for optimizing tumor response and time to resistance for the combination. To examine this more closely, we used a pharmacokinetic/pharmacodynamic (PK/PD) modeling approach, coupling one-compartment PK models of two hypothetical drugs based on set synchronous or asynchronous (offset) schedules with an evolutionary model of tumor clone growth. We simulated four tumor subpopulations representing binary resistance to one or both drugs, using an exponential growth model with growth penalties based on drug concentrations. We used the model to simulate the effects of pairs of antagonistic, synergistic, and additive drugs on the growth of sensitive and resistant populations in a tumor. Final tumor volume and resistant population were used to compare the efficacy of various drug schedules. As expected, the effect of a drug interaction—either synergistic or antagonistic—is greatest when dosing is synchronous, as this results in the greatest simultaneous drug concentration. The effect of a drug interaction is proportional to the sensitive population size, so the effect of drug interactions decreases over time as the sensitive population is eliminated. Intuitively, the final tumor volume decreases as the strength of a synergistic interaction increases until the sensitive population is eliminated. The resistant populations are unaffected by the strength of the interaction for both antagonistic and synergistic combinations. Resistant populations are not affected by interactions between drugs to which they are resistant, so the growth of resistant populations over time is independent of drug interactions. Crucially, for effective drugs—that is, drugs that eliminate the sensitive population—synergy and antagonism converge to additivity as the sensitive population dies out because the remaining resistant populations are not affected by drug interactions. As synergistic and additive drug combinations are equivalent in the long-term, synergy and asynchronous dosing could be used to limit toxicity without sacrificing efficacy. The evolution of resistance also explains why in vitro synergy or antagonism may not translate in vivo. Taken together, our work provides several unintuitive insights about combination drug scheduling with practical implications for therapeutic design. Citation Format: Madison Stoddard, Andrew Chen, Lin Yuan, Debra Van Egeren, Dean Bottino, Arijit Chakravarty. Impact of drug combination schedules on the evolution of tumor resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4310.

Understanding the Missing Links in Hahnemann's Posology for Drug Proving

AbstractHahnemannian drug proving has been reproved and clinically verified in multiple geographical locations in the last two centuries. They continue to be the most reliable and useful proving records even today. However, in absence of daybook of these provings, many practical questions essential for its successful replication have remained unanswered. In this study, we have tried to understand a few of these questions such as why Hahnemann did not mention the doses employed in his drug proving. What were his actual instructions for the repetition of doses to the provers? In 50 years, Hahnemann's propositions for posology in drug proving changed several times. Which phase and posology have contributed maximally to the existing literature? Last but not least, is the drug proving in 30th potency ‘the best and final plan’ of Hahnemann? In the process of finding answers to these questions, some fascinating facts have emerged. Notably, to prioritise individualisation in drug proving, design drug schedules more often in a successively increasing fashion and lastly, to explore all ranges of potencies for proving till little of novel character could be recorded on subsequent proving of the drug.

Treatment of bone metastases from solid tumors with bone-modifying agents: a web survey of Italian oncologists investigating patterns of practice drug prescription and prevention of side effects

PurposeOptimal use of bone-modifying agents (BMAs) in patients with bone metastases from solid tumors is uncertain in some aspects: the drug choice; the planned treatment duration and long-term therapy; the prevention and management of possible side effects, including renal toxicity, hypocalcaemia, and medication-related osteonecrosis of the jaw (MRONJ).MethodsItalian oncologists were invited to fulfil a 24-question web survey about prescription of BMAs for bone metastases of breast cancer, prostate cancer, and other solid tumors. Prevention and management of side effects were also investigated.ResultsAnswers of 191 oncologists were collected. BMAs are usually prescribed at the time of diagnosis of bone metastases by 87.0% (breast cancer) and 76.1% (solid tumors except breast and prostate cancers) of oncologists; the decision is more articulated for prostate cancer (endocrine-sensitive versus castration-resistant). The creatinine level (32.3%), the availability of patient venous access (15.8%), and the type of primary neoplasm (13.6%) are the most reported factors involved in choice between bisphosphonates and denosumab. Zoledronic acid every 3 months was considered as a valid alternative to monthly administration by 94% of Italian oncologists. Oncologists reported a good confidence with measures aimed to prevent MRONJ, whereas uncertainness about prevention and management of hypocalcemia was registered.ConclusionItalian oncologists showed a high attitude in prescribing bisphosphonates or denosumab at the time of diagnosis of bone metastases, with a large application of preventive measures of side effects. Further studies are needed to investigate some controversial aspects, such as optimal drug treatment duration and long-term drug schedules.

Advancements in Antidiabetic Therapy: An extensive study on the use of Polypills to treat type 2 diabetes

The hallmark of type 2 diabetes (T2DM) is elevated blood glucose levels brought on by insulin resistance or inadequate insulin synthesis. Oral hypoglycaemic medications and insulin therapy are two examples of pharmacological therapies used in conjunction with lifestyle changes like diet and exercise to manage type 2 diabetes. However, because T2DM is a complex disease and requires many drugs to regulate different risk factors, managing the condition can be difficult. Polypills, or cardiovascular fixed-dose combination pills, have the potential to alleviate the pervasive inaccessibility and noncompliance with established medications. Switching from existing individually taken drugs is usually required to begin polypill-based therapy. The impact of polypill treatment across various patterns of previous pharmaceutical regimen is of relevance due to the heterogeneity in usual care. Utilizing a polypill helps streamline drug schedules, lessening patients' burden with pills, and possibly increasing adherence. In type 2 diabetes, when controlling blood pressure, cholesterol, and blood glucose levels frequently necessitates the use of many drugs, this is especially crucial. Recommendations state that those with established cardiovascular disease are probably now receiving aspirin, a statin, and blood pressure (BP)-lowering drugs. It might be reasonable to combine these medications into a cardiovascular polypill for these patients in order to reduce prescription gaps and non-adherence. A sizable portion of individuals suffering from long-term cardiovascular conditions currently use a combination of prescription drugs. Introduce a polypill to high-risk patients to reduce prescription gaps and enhance adherence to recommended therapy

New Approaches for the Treatment of AML beyond the 7+3 Regimen: Current Concepts and New Approaches

Fifty years have passed since the development of the first chemotherapy regimen for treating acute myelogenous leukemia (AML), with the approval in 1973 of the cytarabine daunorubicin (7+3) regimen. Until recently, patients diagnosed with AML had very limited treatment options and depended primarily on chemotherapy in combinations, doses, or schedules of the same drugs. Patients with advanced age, comorbidities, or relapsed or refractory disease were left with no effective options for treatment. New advances in the understanding of the biology and the molecular and genetic changes associated with leukemogenesis, as well as recent advances in drug development, have resulted in the introduction over the last few years of novel therapeutic agents and approaches to the treatment of AML as well as a new classification of the disease. In this article, we will discuss the new classification of AML; the mechanisms, actions, and indications of the new targeted therapies; the chemotherapy combinations; and the potential role of cellular therapies as new treatment options for this terrible disease.

Abstract PR001: Learning to adapt: Rational personalization of adaptive therapy using deep reinforcement learning

Abstract Standard-of-care treatment regimens have long been designed for maximal cell kill, yet these strategies often fail when applied to metastatic cancers due to the emergence of drug resistance. Adaptive treatment strategies have been developed as an alternative approach, dynamically adjusting treatment to suppress the growth of treatment-resistant populations, delaying, or even preventing, tumor progression. Promising clinical results in prostate cancer indicate the potential to optimize adaptive treatment protocols. We propose the application of deep reinforcement learning (DRL) to guide adaptive drug scheduling, and demonstrate that these treatment schedules can outperform the current adaptive protocols in a mathematical model calibrated to prostate cancer dynamics, more than doubling the time to progression. We show that the DRL strategies are robust to patient variability, including both tumor dynamics and clinical monitoring schedules. We demonstrate that the DRL framework can produce interpretable, adaptive strategies based on a single tumor burden threshold, replicating and informing optimal treatment strategies. Given the DRL framework has no knowledge of the underlying mathematical tumor model, this demonstrates the capability of DRL to help develop treatment strategies in novel or complex settings. Finally, we propose a five-step pathway combining mechanistic modeling with the DRL framework to translate this approach to the clinic with limited information for a given patient. Integrating conventional tools to ensure the interpretability of traditionally `black-box' DRL models, we generate personalized treatment schedules that consistently outperform clinical standard-of-care protocols. Citation Format: Kit Gallagher, Maximilian Strobl, Robert Gatenby, Philip Maini, Alexander Anderson. Learning to adapt: Rational personalization of adaptive therapy using deep reinforcement learning [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr PR001.

Concurrent determination of anti-microbial and anti-inflammatory drugs in lachrymal fluid and tissue by LC-MS/MS: A potential treatment for microbial keratitis and its PK-PD evaluation

Unforeseen surfacing of microbial keratitis (MKT) over the years has led to a requisite for promising treatment strategy involving combination of antifungal and antibacterial agents. Subsequently, symptoms associated with MKT including inflammation and watery eyes require treatment with anti-inflammatory agents. Thus, a requirement of functional clinical treatment strategy involving combination of anti-inflammatory corticosteroids (Betamethasone) with antifungal polyene (Amphotericin B, AmB) and antibacterials macrolide (Azithromycin, AZT) and aminoglycoside (Neomycin, NEO). In the ensuing pursuit, a sensitive and fast simultaneous LC-MS/MS method of four drastically different analytes in rabbit tear fluid and cornea was developed and validated as per US-FDA guidelines. The gradient LC set-up was used with C18 column and flow rate of 0.55 mL/min along with short run time of 7 min. The calibration curves showed good linearity over the concentration range of 0.07–300 ng/mL, 1.00–400 ng/mL, 3.00–600 ng/mL and 8.00–900 ng/mL for AZT, AmB, NEO and BEM respectively. The bioanalytical method requires only 10 µL of ocular sample and analytes were extracted with fast protein precipitation with acidic methanol. Finally, the developed method was validated for selectivity, linearity (r2 > 0.99), precision, accuracy, matrix effects, and stability. PK-PD indices and dosing frequency was predicted using Phoenix WinNonlin Software, based on single dose ocular pharmacokinetics and MIC values of AmB, AZT and NEO. According to the PK-PD simulation, S. aureus and E. coli required 6 and 12 instillations of AZT per 24 h, respectively whereas 12 instillation of NEO requires per 24 h for S. aureus. The result suggests that to minimize antimicrobial resistance; drug, dose and dosing schedule depend upon the pathogen as well as the strain.