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IC Regimen: Delaying Resistance to Lorlatinib in ALK Driven Cancers Using Repurposed Itraconazole and Cilostazol

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11 June 2024

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12 June 2024

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Abstract
This paper presents data supporting the IC Regimen for potentiating the effectiveness of lorlatinib in treating ALK positive cancers, and specifically non-small cell lung cancer. Lorlatinib is an effective treatment for ALK driven non-small cell lung cancer and other ALK driven cancers. Lorlatinib inhibits ALK kinase and achieves good brain tissue levels, a common site for metastases in lung cancers. However, resistance to lorlatinib usually supervenes and the cancer awakens and starts growing again, resistant to lorlatinib. This paper analyses data indicating that adding two common generic drugs, itraconazole and cilostazol, to lorlatinib treatment may delay resistance development. Itraconazole is marketed worldwide as a generic antifungal drug that also inhibits Hedgehog signaling, CYP3A4, and the p-gp efflux pump. Cilostazol is a generic anti-thrombosis, phosphodiesterase 3 inhibiting drug that carries minimal bleeding risk. Cilostazol may enhance lorlatinib by deprivation of trophic growth factors supplied by platelets. Itraconazole may enhance lorlatinib effectiveness by reducing or stopping a Hedgehog centered amplifying feedback loop with ALK kinase. The combination of metastatic non-small cell lung cancer being a low-survival disease and the general safety itraconazole plus cilostazol augmentation, make a clinical trial of this trio worthwhile.
Keywords: 
Subject: Medicine and Pharmacology  -   Oncology and Oncogenics

1. Introduction

This paper shows how two drugs from general medical practice can be repurposed to potentially improve treatment of some forms of lung cancer.
ALK refers to anaplastic lymphoma kinase. Lorlatinib is an ALK inhibitor with good brain tissue penetration, effective in treating cancers having increased drive by ALK overexpression or overactivity [1,2,3]. Non-small cell lung adenocarcinomas (NSCLC), large cell neuroendocrine lung cancer (LCNEC), glioblastoma, neuroblastoma, anaplastic large cell lymphoma, and anaplastic thyroid carcinoma are several of the cancers that are found commonly to have a growth drive at least partially mediated by ALK, aberrantly expressed by overproduction, by constitutive activating mutations, by activating fusions, or by mutated forms of ALK [4,5].
Inhibition of lorlatinib’s main catabolic enzymes, CYP3A and UGT1A4, resulted in a 16 times elevation of mouse brain tissue levels, but that elevation did not seem to effect the animals [6]. Lorlatinib has a wide therapeutic index.
Common side effects of lorlatinib include edema, headache, hyperlipidemia, and neuro-psyche impairments - all of which can usually be treated by standard means but may require dose reduction [7,8,9].
Non-pathological ALK is activated by any one of several endogenous ligands binding to the ALK extracellular domain. Such binding triggers dimerization and autophosphorylation of the ALK intracellular domain that in turn triggers a downstream signaling chain. Pathological ALK can be activated this way too but has other activations mechanisms as well, vide infra.
In general, a cancer’s resistance to pharmacological ALK inhibition occurs by one or more of these paths: [1,5,10,11,12]
i) via activation of bypass survival pathways, EGFR or the insulin-like growth factor (IGF) for example, or
ii) further mutation of ALK, or
iii) gene amplification, or
iv) simple compensatory increases in ALK expression, or
v) by upregulation of cell exporter pumps.
Pharmacological inhibition of ALK itself will provoke a homeostatic upregulation of ALK protein expression [10].
In a quarter of lorlatinib resistance cases the origin of resistance is unknown. But resistance supervenes overtime, leading to clinical relapse [12,13].
This paper recounts data showing the mechanisms by which two repurposed drugs from general medical practice- itraconazole and cilostazol- intersect with ALK signaling and lorlatinib action to potentially augment lorlatinib effect or delay a cancer’s development of resistance to lorlatinib.
Table 1A and Table 1B list some of the most basic pharmacological parameters of the three IC Regimen drugs.
The three Prefaces above refer to basic principles of metastatic cancer treatment behind the IC Regimen, enunciated more fully elsewhere [14,15]. The core of these principles, as encapsulated in the three aphorisms, are the need for multidrug approaches with drugs with risk that, by design, are low, but not without risk.

2. ALK

ALK is composed of an extracellular region, a single transmembrane helix and an intracellular tyrosine kinase domain [16,17]. When ALK oligomerizes in absence of ligand retention in cytosol result [18]. ALK oligomers or dimers activate the kinase domain triggering downstream signaling of Ras/Raf/MEK/ERK1/2 and JAK/STAT pathways [19]. ALK is essential for embryological development but is not usually expressed in adult tissue.
Side effects of slowed speech and other neurocognitive problems are common as are elevated cholesterol and triglycerides. Side effects tend to resolve quickly after stopping lorlatinib [20]. Resistance develops often within the first few years of an initially responsive ALK positive NSCLC [21]. MYC transcription factor drives ALK expression, and ALK signaling drives MYC expression thus forming a potential mutually reenforcing amplification feedback loop [22,23]. Other ALK related amplification loops are detailed below.

3. Hedgehog

Hedgehog signaling (Hh) is commonly upregulated in ALK positive cancers [24]. Hh signaling commonly becomes a link in a cancer’s growth and survival signaling, engaged as part of the signaling chain initiated by other growth driving systems [25,26,27]. Then end result of the Hh system is creation of Gli transcription factors that bind to their consensus binding sites, either a Gli-R that represses, or a Gli-A that activates transcription.
NPM-ALK fusion protein in lymphoma results in increased Hh signaling. NPM-ALK is a constitutively active fusion ALK in some lymphomas that enhances creation of transcription activating Gli-A [28].
A simplified overview of Hh signaling complex and its relationship with ALK expression is graphically presented in Figure 1 and recounted here. Four core proteins of Hh signaling, Gli, Hh, Ptch and Smo, interact in Hh signaling. Gli is the central element that by differential processing either represses or promotes target gene transcription.
Ptch has an extracellular receptor domain and an intracellular effector domain. In the quiescent, unliganded Hh signaling complex, Ptch prevents Smo from access to Gli, allowing Gli’s sequential phosphorylation by protein kinase A (PKA) ➡ glycogen synthase kinase 3-beta ➡ casein kinase I, creating Gli repressor form (Gli-R) that then binds to consensus DNA areas to repress expression and translation of the many Hh target genes, one of which is for Gli itself, forming feedback cycle 1 in Figure 1. Thus creating within Hh signaling and Gli, a bistable switching system with potential positive amplifying feedback loop within that system [29,30].
Thus Gli signaling tends to have two stable states,
i) Gli-A as promoter increases Gli transcription, and ii) Gli-R as repressor, represses Gli transcription.
After the Hh signaling complex binds an Hh ligand, Ptch is replaced by Smo that allows release of Gli without undergoing the phosphorylation chain. Gli then becomes an active translation promoter, Gli-A.
Dozens of stimulating or inhibiting factors influence this simplified schematic, and other post-translational Gli modifications in addition to the above mentioned phosphorylation chain. High GLI-A to GLI-R ratios are mainly associated with proliferation, increased survival, and stem cell self-renewal, while low ratios favor differentiation and quiescence [29,31,32].

4. ALK and Hh form a Cyclic Amplifying System

Hh and ALK systems can interact. Hh is amplified in ALK positive lymphoma where silencing GLI inhibits growth of ALK driven lymphoma cells [33,34]. ALK inhibition suppresses functioning GLI transcription factor and active ALK signaling triggers increase in Gli-A, thus forming a second amplification feedback loop within the ALK Hh system, as depicted as feedback cycle 2 in Figure 1 [28,33,35].
Hh signaling itself contributes to growth and neuroendocrine lineage selection in neuroendocrine lung cancers [36,37,38]. Ishiwata et al showed that Gli inhibition or quantitative reduction suppressed growth in an experimental model of LCNEC [39]. Hh is best recognized as a driver of basal cell carcinoma and medulloblastoma, but is seen in some cases of breast, lung, prostate and other cancers as well.
So we see two amplification feedback loops within the ALK/Hh system, designated 1 and 2 in Figure 1. Hh functioning diminishment therefore has potential to allow lorlatinib to remain effective.

5A. Hh and the Repurposed Drug Itraconazole

In the antifungal role, itraconazole inhibits fungal lanosterol 14-α-demethylase, preventing ergosterol that is required for fungal wall formation. In the anti-cancer role itraconazole inhibits Hh signaling by binding Smo [40,41,42,43,44].
A few other intersections of Hh with ALK:
1. Hh inhibition with vismodegib or itraconazole clinically suppresses, but often incompletely so, growth of basal cell carcinoma [40,45,46]. Approximately, 85% of sporadic basal cell carcinoma carry mutations in Hh pathway genes, especially in PTCH, SUFU and SMO genes, which lead to the aberrant activation of GLI.ALK and Hh are also related in basal cell carcinomas. Basal cell carcinoma generally has >250 fold increase in ALK and its ligands, pleiotrophin and midkine, compared to normal epidermis. Stronger expression of phosphorylated ALK in basal cell carcinoma tumor nests than normal skin was observed by immunohistochemistry [47].
2. An ABCG2 binding site for GLI resides in the ABCG2 consensus sequence promoter. Accordingly, Gli-A increases ABCG2 (synonymous with BCRP) expression, a stem cell marker in NSCLC [48,49,50].

5B. Itraconazole Caveats

Itraconazole’s absorption is erratic. It requires an acidic environment for ideal absorption. Proton pump inhibitors must be avoided and itraconazole must be given with an acidic beverage like Coke™, pH2, or orange juice. It is difficult to draw conclusions from studies that did not assure these conditions.
Lorlatinib is metabolized by CYP3A4 and UGT1A4m. Itraconazole increases Cmax by 24% and systemic exposure to lorlatinib by its strong CYP3A3 inhibition [51,52]. The combination of lorlatinib plus itraconazole therefore requires monitoring for adverse events from increased lorlatinib levels. Lorlatinib cellular efflux is partially mediated by p-pg (P-glycoprotein, synonymous with MDR1 and ABCB1). Itraconazole also inhibits p-gp [53,54,55]. Together these two attributes raise risk of increased CNS side effects by virtue of both elevation of blood level through CYP3A4 inhibition and by lowering blood-brain barrier drug efflux by p-gp inhibition. The lorlatinib package insert from the manufacturer states “Avoid concomitant use of LORBRENA [lorlatinib] with a strong CYP3A inhibitor. If concomitant use cannot be avoided, reduce the LORBRENA dosage” [https://lorbrena.pfizerpro.com/].
In addition to Hh signaling, itraconazole inhibits an unusually wide range of human enzymes and signaling systems:
  • p-gp = MDR1 = ABCB1 [55]
  • CYP3A [56]
  • ABCG2 = BCRP [55,57].
  • Human 11β-hydroxysteroid dehydrogenase 2 [58]
  • Human Niemann-Pick C1 lysosomal protein [59,60]
  • Human mitochondrial protein voltage-dependent anion channel 1 (VDAC1) [59,60]
  • Human CEBPB, a transcription factor [61]
  • 5-lipoxygenase [62]
  • Wnt signaling [43,63,64,65,66]
However the low incidence of side effects from itraconazole may indicate low degree of inhibition in practice, or the existence of readily engaged cross-covering systems during clinical use that may lower clinical effectiveness during cancer treatment. Also since many commonly used drugs are catabolized by CYP3A4, itraconazole has potential for drug-drug interactions that must be kept in mind when considering what other drugs might be given.
The main side effects of increased lorlatinib systemic exposure are worsening of hypertriglyceridemia, hypercholesterolemia, and psychiatric or cognitive disturbances. These are potentially treatable by standard means but may require lorlatinib dose reduction. Of note here is the potential of cilostazol to lower hypertriglyceridemia, hypercholesterolemia [8,9].

5C. Additional Potential Benefits of Itraconazole

In addition to itraconazole’s actions as antifungal drug and Hh inhibition, several other itraconazole attributes make it an attractive adjunct in treating NSCLC.
1. Itraconazole also inhibits Wnt signaling [43,63,64,65,66], an overactive signaling system contributing to NSCLC growth vigor and treatment resistance [67,68,69,70].
2. Perhaps the most compelling data favoring clinical use of adjunctive itraconazole are clinical experiences with itraconazole as adjuvant to NSCLC surgery or traditional cancer cytotoxic chemotherapy.
i) NSCLC cases in platinum based chemotherapy with itraconazole 200 mg/day, 21 days on, 7 days off, experienced
longer progression free survival but the same 1 year survival rate as those in the same chemotherapy without itraconazole [71].
ii) Adding itraconazole (600 mg/day) alone prior to surgery in NSCLC cases, resulted in lung tumor size and perfusion reduction after 14 days of use. Tumor tissue levels of itraconazole exceeded those in plasma [72].
iii) The CUSP9v3 trial that included itraconazole 200 mg twice daily in recurrent glioblastoma showed evidence of benefit [15,73].
iv) Itraconazole 600 mg/day lengthened the PSA doubling time in advanced prostate cancer without lowering androgen levels. Important to note here that 200 mg itraconazole was without effect [74,75].
v) In advanced NSCLC cases given pemetrexed with itraconazole 200 mg/day, 21 days on, 7 days off survived longer than those given pemetrexed alone, 32 versus control 8 months [76].
vi) Itraconazole had a rather dramatic effect in prolonging survival in women being treated for ovarian cancer [77,78]. Given this data from 2014, it is unclear neither why these studies have not been verified or refuted, nor why itraconazole is not routinely used in treating ovarian cancers in 2024.

6. Repurposed Drug Cilostazol

This section reports data on the trophic function of platelets in cancer growth generally and in NSCLC specifically and how deprivation or reduction of platelets’ trophic function by cilostazol may retard NSCLC growth or delay lorlatinib resistance.

6.1. Cilostazol

Cilostazol is an oral drug marketed for treatment of intermittent claudication. It inhibits phosphodiesterase 3 (PDE3) and the adenosine uptake pump. PDE3 mediates the conversion of c-AMP to AMP.
In clinical use for 20+ years, it inhibits platelet aggregation and causes vasodilation when used in treating peripheral arterial and cerebrovascular disease [79,80]. Standard treatments are usually effective for cilostazol side effects of mild headache and diarrhea [81].
Cilostazol inhibits platelet aggregation induced by collagen, ADP, epinephrine, arachidonic acid and other common aggregation or activation stimuli, reducing the number of activated platelets in circulation yet with minimal bleeding risk [82,83,84,85,86].
Given these platelet attributes it is unclear why cilostazol does not carry more of a bleeding risk. About 1 per 100 patient-years of people with a previous stroke treated with cilostazol for secondary stroke prevention will experience a serious bleeding event [87]. Comparative anti-platelet studies show a lower bleeding risk with cilostazol than with aspirin in secondary stroke prevention [88,89,90,91].
Cilostazol is metabolized by hepatic CYP3A4 and 2C19 with circulating half-life about 12 hours. Simultaneous itraconazole use therefore has potential to increase cilastazol’s effects and halflife. Importantly for potential use in NSCLC, bleeding time is not prolonged by cilostazol but is prolonged by aspirin and ticlopidine even though all three show similar antiplatelet effects in ex vivo platelet aggregation inhibition tests [86,92].
The main physiological consequences of cilostazol are reduced vascular smooth muscle proliferation, reduced platelet activation and aggregation [93,94,95]. PDE3 catalyzes reaction cAMP to AMP. PDE3 has high competitive affinity for both cAMP and cGMP but does not catalyse a parallel reaction of cGMP to GMP [96].
The term “platelet activation” refers to a process that prepares or permits platelet degranulation of intracellular contents. Activation occurs with platelet exposure to ADP, thrombin, vitronectin, fibronectin, or thrombospondin-1, as examples. Multiple other factors can trigger platelet activation. Platelet alpha-granules contain dense concentrations of Factors V, IX, XIII, antithrombin, thrombospondin, CXCL1, CXCL4, CXCL5, IL-8, CCL2, MCP-1, CCL3 (MIP-1), CCL5 (RANTES), epidermal growth factor (EGFR), hepatocyte growth factor (HGF), IGF, TGF-beta, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet derived growth factor (PDGF) [97,98,99]. Notably, platelets contain fully 25% of blood borne VEGF [100,101,102]. By sticking to tumor stroma, then releasing their contents, platelets contribute these growth factors to the growing vasculature and the malignant cells themselves [103].
Platelet borne alpha-granules are a rich source of HGF. HGF is the cognate ligand for c-MET. Development of c-MET amplification constitutes one of the resistance mechanisms to lorlatinib [11,104]. Therefore reduction of platelets provision of HGF by cilostazol potentially delays that resistance pathway.

6.2. Trophic Function of Platelets in Cancer:

Platelets play an important multifaceted role in cancer growth and metastasis establishment [105,106,107,108,109,110,111]. Elevated platelet count is a negative prognostic sign across the common cancers [103,112,113]. Specifically in pulmonary LCNEC [114,115] and NSCLC [116,117,118,119,120], a higher platelet-to-lymphocyte ratio (PLR) predicts shorter OS.
Gouban et al and others have reported existence of tumor induced platelet activation, otherwise termed “tumor educated platelets”. This results in a reciprocal relationship where tumors change, educate, condition, platelets that then contribute to tumor growth and dissemination, a relationship documented in several cancers [113,121,122,123]. See schematic representation of this in Figure 2.Thus another positive feedback loop where platelets help a cancer grow and a growing cancer signals the bone marrow to make more platelets and educates those platelets to release growth enhancing factors. This mutually supporting process is depicted in Figure 2. This reciprocal support system is recognized in many common cancers.
Cilostazol inhibited ex vivo platelet-dependent fibrin formation and platelet release of CCL5 and CXCL4 [124].
CCL5 synthesized by NSCLC cells and by their stroma enhance NSCLC growth, metastasis, and trophic myeloid cell chemotaxis to tumor [125,126,127,128,129]. The question of to what degree deprivation of platelets’ contribution of this cytokine will effect growth is unknown. Regarding CXCL4, NSCLC cases with higher CXCL4 levels had worse overall and disease-free survival [130].
By whole-blood flow cytometry, leukocyte-platelet aggregates mediated by platelets’ surface P-selectin depend on degranulation of alpha-granules [131]. Preliminary evidence implicates these leukocyte-platelet aggregates in facilitating metastases [132,133,134].
Cilostazol decreases both circulating and platelet released P-selectin [135,136,137]. Plasma P-selectin is elevated in NSCLC, where greater elevations predispose to vascular thrombosis events compared to those with lesser elevations [138]. Treatment with cilostazol 100 mg bid lowered blood platelet-neutrophil aggregates and plasma P-selectin in peripheral artery disease [139,140]. Platelets are a major repository of P-selectin, an adhesion molecule expressed on the platelet surface [141,142,143]. Platelet-malignant cell adhesion is mediated i.a. by P-selectin [144,145,146].
P-selectin is expressed also on vessel endothelial cells where it mediates platelet and neutrophil adhesion. Interestingly, cilostazol decreased P-selectin expression on endothelial cells as well [147]. Cilostazol reduces adverse cardiovascular events in humans also by effects on vessel wall endothelium and triglyceride reduction, independently of any platelet effects [148,149,150,151].
The second-most remarkable finding vis a vis platelets, cilostazol and cancer, was an in vitro study by Suzuki et al who showed that cilostazol inhibited in vitro invasion of pancreas cancer cells by reducing those cells’ synthesis of matrix metalloproteinase-9 [152]. Their conclusion was to “...propose that antiplatelet agents are applicable in clinical treatment to inhibit metastasis of malignant tumor cells.”
Perhaps the most remarkable finding regarding platelets in cancer physiology is that platelets inject their own mitochondria into cancer cells, demonstrated in osteosarcoma and breast cancer but probably universally throughout the common cancers [153,154,155,156]. Such transfer was platelet-to-cancer cell adherence dependent and adherence was mediated in part by P-selectin. Cilostazol inhibits P-selectin release but it is unknown if that is sufficient to limit platelet mitochondrial transfer to a cancer. If such bird-like feeding of cancer cells occurs throughout the common cancers this would be a finding of the first magnitude with fundamental treatment consequences. Platelet transfer of viable, respiratory competent mitochondria also occurs in normal wound healing, forming in part, the basis for platelet facilitation of wound healing [157,158,159].
Caveat: Since i) aspirin, ii) cilostazol, and iii) the clopidogrel-group of antiplatelet drugs all reduce platelet aggregation and mediate platelets’ contribution to thrombosis by their respective three different mechanisms, we cannot yet assume that data reviewed here for cilostazol would apply to other thrombosis inhibiting medicine in current clinical use.
The reviewed data in this platelet section imply two different effects of a growing cancer on platelets:
i) increased absolute platelet count and elevated PLR imply communication of a cancer with bone marrow, and
ii) activation and attraction of platelets to a growing cancer imply a cancer cell mediated change in platelet function.

7. Discussion

Many common cancers have ALK overdrive as one of the suite of their growth driving elements, thus making pharmacological or other ALK inhibition a potential “tumor agnostic target” [160,161]. This implies potential usefulness of adding adjunctive IC Regimen to lorlatinib treatment of other ALK positive cancers like glioblastoma or neuroblastoma.
Aspirin inhibits platelet aggregation and activation via COX-1 inhibition. Cilostazol inhibits platelet activation by PDE 3 inhibition. The resultant interference with platelet function differs also evidenced by the greater bleeding risk with aspirin use compared to cilostazol.
We do not know yet to what degree, or even if, cilostazol will limit platelet delivery of growth and metastasis stimuli to a growing cancer in clinical practice. Regarding concerns of the absence of any clinical trials of cilostazol added to cancer treatment, we can balance that absence with:
i) the few papers that do show cancer growth retarding effect of cilostazol in animal models [96,152,162,163,164,165,166,167,168]
ii) the strength of rationale for its use.
iii) the demonstrated low risk of bleeding or other adverse events.
In terms of the Second Preface to this paper, lorlatinib would be the decisive operation, itraconazole and cilostazol the shaping operations.
As in Figure 1, Hh has two amplification feedback loops that would potentially increase strength of ALK expression and signaling, making Hh inhibition a particularly attractive physiological point to deepen inhibition of ALK alongside lorlatinib.
Since shifting dependence on ALK to alternate or parallel signaling forms one of the resistance pathways to lorlatinib, and platelets comprise a trophic source of many of these parallel signaling agonists, cilostazol has potential to delay lorlatinib resistance.

8. Conclusions

Itraconazole and cilostazol added to lorlatinib may retard development of lorlatinib resistance. The potential of itraconazole increasing lorlatinib levels and thereby creating adverse events merits caution and close monitoring.
Abbreviations: ALK, anaplastic lymphoma kinase; Hh, Hedgehog signaling complex; IGF, insulin-like growth factor; LCNEC, large cell neuroendocrine lung cancer; NSCLC, non-small cell lung adenocarcinomas; PDE3, phosphodiesterase 3;

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Figure 1. The core process of itraconazole’s interaction with ALK and Hh signaling. Many intermediate steps, many cofactors that inhibit, many cofactors that enhance, the isoforms of Gli, that influence the end resulting effect on Gli and of Gli are omitted. 1 refers to the bistable feedback cycle within Hh signaling. 2 indicates the positive feedback loop between ALK and Hh.
Figure 1. The core process of itraconazole’s interaction with ALK and Hh signaling. Many intermediate steps, many cofactors that inhibit, many cofactors that enhance, the isoforms of Gli, that influence the end resulting effect on Gli and of Gli are omitted. 1 refers to the bistable feedback cycle within Hh signaling. 2 indicates the positive feedback loop between ALK and Hh.
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Figure 2. Mutually supporting relationship between a cancer and platelets Platelet alpha-granules contain dense concentrations of Factors V, IX, XIII, antithrombin, thrombospondin, CXCL1, CXCL4, CXCL5, IL8, CCL2 (MCP-1), CCL3 (MIP-1α), CCL5, EGFR, HGF, IGF, TGF-beta, VEGF, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF). P-selectin resides on platelets’s surface. The shown growth factors are representative of a large array of them. The diagram indicates cilostazol inhibits platelet activation but this effect is not absolute.
Figure 2. Mutually supporting relationship between a cancer and platelets Platelet alpha-granules contain dense concentrations of Factors V, IX, XIII, antithrombin, thrombospondin, CXCL1, CXCL4, CXCL5, IL8, CCL2 (MCP-1), CCL3 (MIP-1α), CCL5, EGFR, HGF, IGF, TGF-beta, VEGF, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF). P-selectin resides on platelets’s surface. The shown growth factors are representative of a large array of them. The diagram indicates cilostazol inhibits platelet activation but this effect is not absolute.
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Table 1A. General medical use and use during lorlatinib treatment in NSCLC/LCNEC Hh, Hedgehog signaling complex.
Table 1A. General medical use and use during lorlatinib treatment in NSCLC/LCNEC Hh, Hedgehog signaling complex.
drug general medical use with lorlatinib
itraconazole anti-fungal Hh, p-gp, 3A4 inhibition
cilostazol thrombosis prevention growth factor deprivation
Table 1B. Basic pharmacological parameters of the IC Regimen drugs ⇧LFT = increased liver transaminases; T1/2 times are approximate and vary from individual to individual.
Table 1B. Basic pharmacological parameters of the IC Regimen drugs ⇧LFT = increased liver transaminases; T1/2 times are approximate and vary from individual to individual.
drug T1/2 metabolism
by		 inhibition of side effects
itraconazole 1 d 3A4 3A4, p-gp ⇧LFT
cilostazol 12 h 3A4, 2C19 none headache, diarrhea
lorlatinib 1 d 3A4, glucuronidation none hyperlipidemia,
neuro-psyche
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