The study began with an analysis of KYNU’s crystal structure to map the residues that line its catalytic pocket, an exercise complemented by an AlphaFold-predicted full-length model that allowed the researchers to assess the enzyme’s architecture beyond the crystallized fragment. KYNU is a hydrolase in the kynurenine pathway, the major route by which the essential amino acid tryptophan is catabolized in mammals. The pathway has attracted intensifying attention in cancer biology because its intermediates modulate immune surveillance, oxidative stress, and cell proliferation, and because altered tryptophan metabolism has been documented in breast cancer patients as far back as the late 1960s. Kynurenine 3-monooxygenase, another enzyme on the same pathway, was previously shown to drive TNBC progression through beta-catenin signaling, while reduced KYNU expression has been linked to restrained proliferation in cutaneous squamous cell carcinoma. What remained poorly defined until now was whether pharmacologically targeting KYNU-mediated inflammatory signaling could produce a therapeutic effect in TNBC itself.

To find molecules capable of engaging the KYNU active site, the team performed a diversity-based high-throughput virtual screen of the ChemBridge compound library, ranking candidates by docking energy and then filtering them through protein–ligand interaction profiling and predicted ADMET properties, which describe a compound’s absorption, distribution, metabolism, excretion, and toxicity. The computational pipeline did not stop at static docking. Shortlisted complexes were subjected to molecular dynamics simulations in GROMACS, a widely used open-source package that tracks the motion of atoms over time under realistic physical forces, allowing the researchers to observe whether candidate ligands remained seated in the binding pocket or drifted away as the protein flexed. Binding free energies were then estimated with the gmx_MMPBSA tool, an end-state free energy method that decomposes the thermodynamic contributions of a protein–ligand complex and is regarded as a more rigorous indicator of affinity than docking scores alone. The lead compound KS79356 stood out with a docking score of −7.8 kcal/mol, exceptionally stable interaction geometry maintained at a root-mean-square deviation of approximately 0.075 nanometers, and a calculated binding free energy of −23.93 kcal/mol, figures that together indicated a durable and energetically favorable engagement with the enzyme.

Experimental validation followed in three cell lines: SUM159 and MDA-MB-231, both established TNBC models, and HBL-100, a non-tumorigenic breast cell line used to assess selectivity. KS79356 inhibited KYNU enzymatic activity with a half-maximal inhibitory concentration of 63.7 nanomolar, a potency that places the compound in the same range as many clinically approved enzyme inhibitors. When tested on cell proliferation, the molecule suppressed the growth of SUM159 cells with a GI50 of 233 nanomolar and MDA-MB-231 cells with a GI50 of 450.8 nanomolar, while sparing HBL-100 cells to a markedly greater degree, a differential toxicity profile that suggests the compound’s effects are concentrated in malignant tissue rather than healthy breast epithelium. The authors note that the compound also carried favorable ADMET characteristics predicted by a machine learning platform designed to evaluate large chemical libraries, an early but encouraging sign for downstream developability.

The mechanistic heart of the study lies in what KS79356 does to inflammatory signaling. Tumor necrosis factor alpha, or TNF-α, is a pro-inflammatory cytokine that activates the transcription factor nuclear factor kappa B, NFκB, a master regulator of survival, proliferation, and immune genes whose chronic activation in tumors promotes growth, metastasis, and chemotherapy resistance. NFκB signaling in turn drives expression of CD44, a cell surface glycoprotein best known as a marker of cancer stem-like cells that promotes tumorigenicity, cell motility, hyaluronan production, and metastatic seeding in bone, and which has repeatedly been associated with poor prognosis in breast cancer. CD44 signaling feeds forward into Akt, a kinase central to the phosphatidylinositol 3-kinase survival pathway, creating an axis — TNF-α to NFκB to CD44 to phosphorylated Akt — that functions as a self-reinforcing engine of tumor aggressiveness. Using Western blot analysis of phosphorylated proteins, the researchers showed that KS79356 downregulated TNF-α–induced phosphorylation of NFκB, suppressed CD44 expression, and reduced Akt phosphorylation in TNBC cells, effectively cutting the communication lines along which inflammatory signals translate into malignant behavior.

The functional consequences of that signaling shutdown were substantial. Treated TNBC cells showed reduced proliferation, diminished capacity to invade through extracellular matrix, and a striking impairment in trans-endothelial migration, the process by which cancer cells squeeze through the endothelial lining of blood vessels to enter the circulation and seed distant metastases. Trans-endothelial migration is one of the earliest and most decisive steps of the metastatic cascade, and its inhibition suggests that KYNU blockade could, in principle, limit not only primary tumor growth but also the spread that makes TNBC lethal. At the same time, flow cytometric analysis revealed that KS79356 induced both early and late apoptosis, pushing cancer cells down programmed death pathways rather than merely halting their division. The combination of cytostatic and cytotoxic effects, delivered through a single upstream metabolic target, illustrates the appeal of enzyme inhibitors that sit at convergence points of multiple oncogenic pathways.

The choice of KYNU as a target also connects the work to a broader and rapidly expanding literature on the kynurenine pathway in cancer immunology. The pathway’s metabolites influence both innate and adaptive immunity and have been implicated in immune-related diseases ranging from autoimmune endocrinopathies to chronic inflammation. In tumors, kynurenine pathway activity can help create an immunosuppressive microenvironment, and the pathway has been described as presenting multi-faceted metabolic vulnerabilities that cancer cells cannot easily compensate for. Reviews of clinical research and trials in breast cancer have highlighted the kynurenine pathway as an emerging therapeutic frontier, and the present study is among the first to move from that associative evidence to a chemically validated, mechanistically annotated inhibitor in TNBC models. The authors position KYNU itself as a novel therapeutic target, distinguishing their approach from earlier efforts aimed at other pathway enzymes such as indoleamine 2,3-dioxygenase and kynurenine 3-monooxygenase.

The computational methodology deserves attention in its own right, both for its rigor and for what it suggests about the future pace of drug discovery. The study’s pipeline — structure-based virtual screening, interaction profiling, molecular dynamics in GROMACS, and MM/PBSA free energy calculations — represents a now-standard but still powerful strategy for identifying chemical starting points without the expense of screening hundreds of thousands of compounds experimentally. The team has deployed similar approaches previously, including the identification of dual PI3K/AKT pathway inhibitors for acute myeloid leukemia and a selective TGFβ receptor II kinase inhibitor for breast cancer, and the same group’s earlier work on inflammatory attenuation via the Akt/NFκB pathway foreshadowed the mechanistic hypothesis tested here. The convergence of those threads in KS79356 illustrates how iterative, computationally guided campaigns can accumulate mechanistic insight across related signaling pathways and disease contexts.

Important caveats remain. All of the reported efficacy data derive from cell culture; no xenograft, syngeneic, or patient-derived models were included, and no pharmacokinetic or toxicity studies in animals have been performed. TNBC is notoriously heterogeneous, and the two cell lines used, while among the most widely studied, do not capture the full molecular diversity of the disease, including the immune-cold and immune-hot subtypes that respond differently to existing immunotherapies such as the atezolizumab and pembrolizumab combinations approved in recent years. The nanomolar GI50 values observed in vitro will need to translate into achievable and tolerable plasma exposures in vivo, a hurdle that eliminates many promising enzyme inhibitors. Nevertheless, the selectivity against HBL-100 cells, the clean biochemical potency, and the coherent mechanistic story linking KYNU inhibition to reduced NFκB–CD44–Akt signaling give the compound a credible foundation for preclinical development.

For a disease that accounts for roughly fifteen to twenty percent of breast cancers and disproportionately affects younger women and, in some populations, carries a hereditary burden linked to BRCA mutations, every new molecular vulnerability matters. The current therapeutic arsenal for metastatic TNBC — anthracyclines, taxanes, platinum agents, antibody–drug conjugates such as sacituzumab govitecan, and immune checkpoint inhibitors — has extended survival but rarely changes the long-term trajectory of the disease. A metabolic enzyme inhibitor that simultaneously blunts inflammatory signaling, stem-like cell marker expression, survival kinase activity, invasion, and intravasation would represent a genuinely different modality, one that attacks the tumor microenvironment’s inflammatory fuel supply rather than its DNA or microtubules. The King Khalid University team, funded through the institution’s Large Research Groups Program and supported by collaborators at SMARTBIO LABS in Chennai and Si-BIOLEAD in Arkansas, has provided the first pharmacological proof of concept that KYNU can be drugged to antitumor effect. The next chapter — confirming those effects in animal models and optimizing KS79356’s drug-like properties — will determine whether this computational lead can complete the long journey from docking screen to clinic.

The eIF4E protein sits at the very top of the protein-manufacturing assembly line in every cell. It recognizes the distinctive seven-methylguanosine cap at the front end of messenger RNAs and recruits the rest of the translation initiation machinery, the eIF4F complex, which includes the large scaffold protein eIF4G and the helicase eIF4A. When eIF4E is hyperactivated—a situation documented in colorectal, breast, bladder, and lung cancers—it selectively boosts the translation of mRNAs encoding growth drivers such as Cyclin D1, c-Myc, VEGF, and Survivin, fueling proliferation, invasion, metastasis, and resistance to chemotherapy. Two oncogenic signaling highways keep eIF4E revved up: the ERK-MNK kinase cascade phosphorylates eIF4E on Ser209, increasing its grip on capped transcripts, while the PI3K-AKT-mTOR axis phosphorylates the inhibitory protein 4E-BP1, prying it off eIF4E so that eIF4E can clasp eIF4G and start translation.

Drug developers have tried for two decades to sever this interface. Ribavirin, an antiviral nucleoside, mimics the mRNA cap and binds eIF4E with only micromolar affinity. 4EGI-1, a classic eIF4E/eIF4G interaction blocker, works at a half-inhibitory concentration of roughly 25 micromolar and has been associated with myelosuppression and liver toxicity. 4E1RCat suffers from poor solubility and a short plasma half-life, while the more recent biphenyl inhibitor i4EG-Bip simply does not grip eIF4E tightly enough. Part of the problem is structural: both the cap-binding pocket and the eIF4E/eIF4G interface are large, shallow binding grooves that offer few of the deep, well-defined pockets medicinal chemists prefer. Many cap-mimetic inhibitors are also negatively charged purine derivatives that cross cell membranes poorly, undermining their activity inside cells.

The research team, led by Yuxi Lin, Xiaoyi Bai, and Dayong Shi of Shandong University, took a structure-guided route around this obstacle. By analyzing how 4EGI-1, 4E1RCat, and i4EG-Bip dock into the eIF4E/eIF4G binding pocket, they noticed two stabilizing features worth preserving: a thiazolyl hydrazone core that engages in a π-π stacking interaction with the residue Phe47, and a phenyl ring that makes a π-alkyl contact with Ile63. They also spotted a liability—an exposed nitro group that experienced charge repulsion with the eIF4E S2 pocket and posed metabolic and safety risks. Applying bioisosteric replacement principles, the chemists synthesized 75 new thiazolyl hydrazone derivatives across six structural series, systematically swapping substituents such as methoxy, fluoro, chloro, hydroxyl, tert-butyl, trifluoromethyl, and trifluoromethoxy groups on two aromatic rings.

Screening those compounds against the eIF4E/eIF4G interaction at 10 micromolar yielded a clear pattern: members of the b-series, bearing a para-trifluoromethyl group on one ring, and the d-series, carrying hydroxyl groups, were the strongest inhibitors. Surface plasmon resonance confirmed direct, tight binding to purified eIF4E for eleven of the hits. The standout was b14, which carries a trifluoromethyl group on one phenyl ring and a trifluoromethoxy group on the other. Its equilibrium dissociation constant was measured at 2.15 × 10⁻⁷ M—about ten times tighter than 4EGI-1, which registered in the low micromolar range. Molecular docking explained why: b14’s thiazole ring forms π-alkyl interactions with Arg61, its two phenyl rings anchor against Ile63 and Lys49, fluorine atoms from the trifluoromethyl group hydrogen-bond with Lys49 and Lys54 in the S2 pocket and form a halogen bond with Asn59, and the trifluoromethoxy fluorines hydrogen-bond with Ser83, locking the molecule into the binding groove from multiple directions at once.

Crucially, cellular thermal shift assays showed that b14 penetrates living cells and stabilizes intracellular eIF4E, addressing the permeability failures that plagued earlier cap-mimetics. In proliferation assays across HCT116 colon carcinoma, A549 lung carcinoma, HeLa and SiHa cervical carcinoma, and SK-OV-3 ovarian carcinoma cells, b14 inhibited growth with half-inhibitory concentrations between roughly 10 and 37 micromolar while sparing the non-tumorigenic H8 control cell line up to about 41 micromolar—a selectivity window that compares favorably with 4EGI-1, which showed essentially no differential toxicity between tumor and normal cells. Beyond killing cells outright, b14 curtailed HeLa cell colony formation, cut wound-healing migration, and reduced total vessel length by 43 percent in an endothelial tube-formation assay, hinting at anti-angiogenic potential.

The mechanism of action unfolded at multiple levels. b14 lowered the phosphorylation of eIF4E on Ser209 in a dose-dependent manner and, intriguingly, also dampened ERK phosphorylation, suggesting feedback regulation within the ERK-MNK-eIF4E axis. It simultaneously reduced phosphorylation of AKT, mTOR, and 4E-BP1, tipping the balance toward 4E-BP1 remaining bound to eIF4E. Co-immunoprecipitation experiments confirmed that b14 selectively disrupted the eIF4E–eIF4G handshake without disturbing eIF4G’s association with eIF4A, and m⁷GTP pull-down assays showed the drug actually strengthened eIF4E’s binding to the brake protein 4E-BP1. The downstream consequences were unambiguous: levels of Survivin, c-Myc, and Cyclin D1 fell, and puromycin incorporation assays revealed a sharp drop in global protein synthesis. Hoechst staining, Annexin V/propidium iodide double staining, and cleaved-PARP immunoblotting together documented that the treated cells were dying by apoptosis.

Perhaps the most novel findings came from following the energy trail. Protein translation consumes an estimated 20 to 30 percent of a eukaryotic cell’s energy budget, and many mitochondrial proteins—including respiratory chain subunits—are synthesized by the very cap-dependent machinery b14 blocks. Consistent with this, b14 treatment elevated reactive oxygen species, collapsed mitochondrial membrane potential as measured by JC-1 staining, and depleted cellular ATP. Quantitative proteomics on the Astral-DIA platform detected 1,014 proteins whose abundance changed after b14 treatment—486 up, 528 down—with pathway enrichment pointing squarely at metabolism, particularly lipid metabolism. Key lipogenic enzymes and regulators, including DECR1 (2,4-dienoyl-CoA reductase 1), LIPA, LDLR, and the master transcription factor SREBP1, were all downregulated. DECR1 is especially notable: it controls fatty acid β-oxidation, is overexpressed in breast cancer, and correlates with poor survival, and its suppression may also sensitize tumor cells to ferroptosis by altering lipid peroxidation. In effect, b14 does not merely switch off the tumor’s protein factories; it starves the tumor of the lipid-building program that rapid growth demands.

The preclinical case closed with animal studies. In female BALB/c nude mice bearing HeLa xenografts, once-daily oral gavage of b14 at 50 or 100 milligrams per kilogram for 30 days shrank tumors in a dose-dependent fashion, with even the lower dose outperforming the positive-control drug ribavirin at 100 milligrams per kilogram. Tumor tissue showed reduced Ki-67 proliferation staining and diminished phosphorylation of both eIF4E and 4E-BP1, mirroring the cellular mechanism. Safety data were striking: mice tolerated a single oral dose of up to 3,000 milligrams per kilogram without mortality or weight loss, and a 14-day subacute regimen at 1,500 milligrams per kilogram produced no behavioral abnormalities, no significant changes in organ weights, no elevation of serum ALT or AST liver enzymes, and no histopathological damage to heart, liver, spleen, lung, or kidney on H&E staining.

The authors caution that b14 is a lead compound, not a medicine—clinical translation will require pharmacokinetic optimization, formulation work, and ultimately human trials. But the study delivers something the field has lacked: proof that a rational, structure-based campaign against the eIF4E/eIF4G interface can yield a cell-permeable, orally bioavailable, selective inhibitor with a clean toxicity profile and a mechanistically coherent, dual-pronged attack on both oncogenic translation and lipid metabolic reprogramming. For a target once written off as undruggable, b14 marks a meaningful step toward making eIF4E a realistic address in precision oncology.

TEAD transcription factors act as the principal downstream mediators of Hippo signaling. In many cancers, dysregulated Hippo-TEAD activity drives cell proliferation, survival programs, and maladaptive tissue growth. Although the TEAD node has been widely viewed as a compelling target, historically, creating selective, drug-like small molecules that effectively inhibit TEAD has been difficult from a medicinal chemistry perspective.

ISM6331 is designed to inhibit TEAD activity using Insilico Medicine’s generative AI-powered discovery platform, Chemistry42. The company describes the compound as a novel and potent pan-TEAD inhibitor, with the goal of achieving selective suppression of pan-TEAD transcriptional signaling. This focus on the TEAD transcription machinery reflects a broader shift in oncology drug development toward pathway-level control rather than single-protein inhibition.

The study being presented is a global, multicenter Phase 1 trial enrolling patients with mesothelioma and other advanced solid tumors. Investigators are evaluating safety and tolerability, along with pharmacokinetics, to characterize exposure and dose behavior. In parallel, the trial includes preliminary assessments of antitumor activity to inform future expansion cohorts and development decisions.

For oncology patients with limited options—particularly in hard-to-treat indications such as malignant mesothelioma—early clinical signals can carry high relevance. Insilico’s leadership emphasized that the selection of ISM6331 for a Rapid Oral slot reflects confidence in the early translational value of the program.

Beyond the molecule itself, the announcement underscores Insilico’s broader strategy: connecting biology, chemistry, and clinical trial outcome prediction through modern machine learning systems. The company frames Chemistry42 as a key component of an end-to-end generative workflow, including target-inspired design and optimization.

If the Phase 1 results demonstrate acceptable safety and meaningful biological activity, ISM6331 could extend TEAD inhibition from preclinical promise into clinical validation. The ESMO Rapid Oral format also suggests that the dataset may include timely, decision-relevant findings for the field.

In summary, ISM6331’s ESMO 2026 Rapid Oral acceptance spotlights a TEAD-centered Hippo pathway program built with generative AI and moving into clinical interpretation. The upcoming presentation will be closely watched by researchers seeking actionable evidence that AI-guided small-molecule design can overcome longstanding constraints in TEAD inhibitor development.

Subject of Research: Hippo signaling / TEAD transcription factors; oncology drug discovery; mesothelioma and advanced solid tumors
Article Title: Insilico Medicine Announces Oral Presentation at ESMO 2026 for Phase 1 Clinical Study of ISM6331 in Mesothelioma and Advanced Solid Tumors
News Publication Date: 2026 (exact date not provided)
Web References: https://www.insilico.com/
References: None provided
Image Credits: Credit: Insilico Medicine

Keywords: Insilico Medicine, ISM6331, pan-TEAD inhibitor, Hippo pathway, TEAD transcription factors, Chemistry42, Phase 1 trial, ESMO 2026, mesothelioma, advanced solid tumors, generative AI drug discovery

This inaugural funding phase awarded two pioneering projects, each granted $50,000 to accelerate discovery efforts and therapeutic validation processes. These projects, helmed by senior investigative scientists at Massey and co-developed in partnership with SBP, underscore the vital integration of state-of-the-art biochemical screening methodologies and medicinal chemistry within academic research settings. By leveraging these cross-institutional synergies, the program seeks to fast-track the drug discovery pipeline from molecular target validation through to preclinical candidate nomination with unprecedented efficiency.

Dr. Robert A. Winn, the Director and Lipman Chair in Oncology at Massey, emphasizes that this collaborative venture inaugurates a novel epoch in translational cancer research. He highlights that the engagement with SBP’s world-renowned assay development and high-throughput compound screening capabilities equips Massey investigators with enhanced tools to expediently translate biological insights into precision oncology agents. This strategic alignment is anticipated to markedly shorten the temporal gap between laboratory breakthroughs and clinical application, addressing the urgent need for novel therapeutics targeting recalcitrant cancer phenotypes.

The two selected projects represent innovative molecular paradigms that target critical and previously underexplored pathways within cancer cells. The first project, titled “Targeting Hsp27-CerS1 Interaction in Solid Tumors,” is spearheaded by Dr. Can Senkal, whose expertise in cellular, molecular, and genetic medicine informs this endeavor. This project focuses on disrupting the interaction between Heat Shock Protein 27 (Hsp27) and Ceramide Synthase 1 (CerS1), a regulatory node implicated in tumor cell survival and apoptosis resistance. By intervening at this juncture, the project aims to destabilize cancer cell proteostasis and potentiate cell death mechanisms selectively within solid tumors.

Complementing this effort, the second project is under the leadership of Dr. Anthony Faber, who occupies the Natalie N. and John R. Congdon, Sr. Endowed Chair in Cancer Research. His work employs a sophisticated cell-based screening platform designed to identify ferroptosis-inducing compounds that impede selenocysteine incorporation. Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has emerged as a promising vulnerability in malignancies resistant to classical apoptotic pathways. By targeting the unique mechanism of selenocysteine incorporation into essential selenoproteins, this approach could irreversibly compromise cancer cell antioxidant defenses and survival.

The integration of novel assay technologies with high-throughput screening paradigms at the Prebys Center for Drug Discovery provides the backbone for these endeavors. This center’s unique capacity for rapid assay development, coupled with robust medicinal chemistry programs, allows investigators to validate small molecules with clinical-grade rigor. Such infrastructure is critical for generating candidate compounds that meet the stringent requirements for advancement into clinical trials, while simultaneously furnishing comprehensive preliminary data packages for robust National Institutes of Health (NIH) and National Cancer Institute (NCI) grant submissions.

M2M’s overarching vision seamlessly aligns with precision medicine principles, aiming to bridge the translational gap by fostering multidisciplinary collaborations between basic researchers, pharmacologists, and medicinal chemists. The initiative’s operational leadership, including Dr. Said M. Sebti and Dr. Shamik Ghosh, acknowledges that this partnership enhances the breadth and depth of therapeutic discovery capabilities at VCU Massey. It introduces breakthrough assay modalities and industry-standard screening processes traditionally accessible only at dedicated drug discovery entities.

Furthermore, this trailblazing program is catalytic in nature, designed not only to identify new pharmacological agents but also to establish robust research pipelines that encourage sustained innovation and therapeutic exploration. By successfully marrying the scientific rigor of academia with the accelerated workflow standards of pharmaceutical discovery, this collaboration exemplifies a new model for addressing the perennial challenge of drug development in oncology. The resulting acceleration from bench to bedside promises to deliver novel therapies with greater efficiency and clinical relevance.

The focus on molecular targets such as the Hsp27-CerS1 axis and the ferroptosis pathway reflects a strategic investment in mechanistically nuanced approaches that exploit unique vulnerabilities within cancer cells. These strategies expand beyond conventional chemotherapy and targeted agents by addressing proteostasis and regulated cell death modalities that have hitherto been difficult to manipulate pharmacologically. This underscores a paradigm shift in drug discovery, wherein molecular precision and pathway selectivity are paramount to achieving therapeutic breakthroughs.

As this collaboration unfolds, it is expected that the resultant data sets and generated compounds will significantly contribute to the global oncology research landscape. Through comprehensive validation and iterative medicinal chemistry optimization at SBP, these projects lay the groundwork for clinical trials targeting solid tumors refractory to existing interventions. The merging of discovery science with translational application embodied in this partnership sets a laudable precedent for future academic-industry alliances aiming to combat cancer with innovative small-molecule therapeutics.

In sum, the VCU Massey and Sanford Burnham Prebys collaborative program is an emblematic initiative that redefines drug discovery within an academic framework. By converging advanced biochemical research with practical drug development methodologies, it facilitates a new frontier in cancer treatment innovation. The program not only accelerates the generation of promising therapeutic candidates but also galvanizes the research community to pursue bold hypotheses grounded in molecular oncology, propelling the field toward transformative patient outcomes.

Subject of Research: Novel small-molecule cancer therapeutics targeting Hsp27-CerS1 interaction and ferroptosis pathways.

Article Title: Advancing Cancer Therapy: VCU Massey and Sanford Burnham Prebys Collaborative Drug Discovery Initiative.

News Publication Date: April 8, 2026.

Web References:
https://mediasvc.eurekalert.org/Api/v1/Multimedia/5b177769-fa05-4974-9e57-1693c81fff5c/Rendition/low-res/Content/Public

Image Credits: VCU Massey Comprehensive Cancer Center

Keywords: Drug discovery, Molecular targets, Cancer therapeutics, Small-molecule agents, Hsp27-CerS1 interaction, Ferroptosis, Selenocysteine incorporation, Translational oncology, High-throughput screening, Medicinal chemistry, Precision medicine, Solid tumors.