一位肿瘤患者的替代药物精准治疗方案

一位年轻的脑胶质瘤患者做了手术，目前无瘤状态，在吃替莫唑胺。她希望用一些副作用小、价格低廉的替代药物，先不上靶向药。无瘤状态吃替代药物，马马虎虎也不失一种办法。
用替代药物也要根据精准检测结果，做精准治疗。
她基因突变情况如下：



一、针对idh1 R132H突变的替代药物
1、《Novel Insights for Inhibiting Mutant Heterodimer IDH1wt-R132H in Cancer: An In-Silico Approach》
这篇论文讲了一种治疗IDH1 R132H 突变的新策略，抑制 IDH1wt-R132H 异二聚体。
通过虚拟筛选，从FDA已经批准上市的药物里，找出了20种对IDH1wt-R132H 异二聚体结合亲和力高的药物。
其中最高的是 Dihydroergotamine 双氢麦角胺。双氢麦角胺是治疗偏头痛的药物，入脑效果好，对她脑胶质瘤正合适。
2、《Long-Term (12-Month) Safety and Tolerability of STS101 (Dihydroergotamine Nasal Powder) in the Acute Treatment of Migraine: Data from the Phase 3 Open-Label ASCEND Study》
这篇论文讲了长期用双氢麦角胺鼻吸入剂的一个临床试验。“ After establishing eligibility, participants could self-administer STS101 5.2 mg as needed for up to 2 doses within 24 h to treat a single migraine attack and up to 12 doses/month.” 一个月最多吸12次，每次5.2毫克双氢麦角胺--相当于6毫克甲磺酸双氢麦角胺（ STS101 is an investigational drug-device combination comprising 5.2 mg dihydroergotamine (DHE) powder (6.0 mg DHE mesylate)），连用12个月，是安全的，耐受良好。
可以参考这个用法。

二、针对ATRX突变的替代药物
ATRX突变可以用parp抑制剂，因此可以用鞣花酸这个parp抑制剂替代药物。
1、鞣花酸与parp结合亲和力高
《Selection of potential natural compounds for poly-ADP-ribose polymerase (PARP) inhibition in glioblastoma therapy by in silico screening methods》
Hence, we aimed to discover potential naturally occurring PARP-1 inhibitors that can be utilized in the treatment of glioma by using multiple in silico tools like molecular docking, absorption, distribution, metabolism, and excretion (ADME) profile, pharmacophore modeling, and molecular dynamic (MD) simulations. Among 43 phytocompounds we screened, two of them (Ellagic acid and Naringin) were discovered to be bound to the catalytic site of PARP-1 with an affinity more remarkable than commercially available PARP-1 inhibitors (Talazoparib, Niraparib, and Rucaparib) except Olaparib. The molecular interactions were analyzed, and data shows that bound entity attained a conserved domain via hydrogen bond interactions, polar interactions, and π-π stacking. Pharmacophore modeling studies showed electronic and steric features of ligands responsible for supramolecular interaction with PARP-1. ADME properties were studied, to assess drug-likeness, hydrophilic nature, hydrophobicity, brain permeability, and oral bioavailability of the natural PARP-1 inhibitors. The simulation study demonstrated the development of a stable complex between Naringin, Ellagic acid, and PARP-1 protein. Moreover, cell culture studies and animal investigations are essential to determine pharmacokinetics and pharmacodynamics.
2、鞣花酸跟化疗联用的临床试验结果表明，鞣花酸虽然是抗氧化剂，但对化疗并无不利影响，反而有益于化疗。
《Support ellagic acid therapy in patients with hormone refractory prostate cancer (HRPC) on standard chemotherapy using vinorelbine and estramustine phosphate》
Background: Recent phase III studies in hormone refractory prostate cancer (HRPC) showed an improvement in terms of overall survival (OS), objective response (OR) and biochemical response (BR); however, chemotherapy is usually accompanied by negative side effects that determines poor quality of life (QoL) and only marginally improves individual clinical response (ICR) in terms of pain relief and performance status. Ellagic acid is a polyphenol that is found in many species of flowering plants. It is an antioxidant that determines apoptosis, down regulation of IGF-II, activates p21 (waf1/Cip1), mediates the cumulative effect on G1/S transition phase and prevents destruction of p-53 gene by cancer cells.
Endpoints: The aim of this study was to assess the effects of ellagic acid support therapy on toxicity, OR, ICR and BR in HRPC patients treated with estramustine phosphate and vinorelbine.
Materials and methods: Patients with HRPC were randomly distributed in two study groups: a control group (group A) who underwent chemotherapy with vinorelbine and estramustine phosphate, and an experimental group (group B) where chemotherapy regimen was associated with ellagic acid.
Results: The mean number of chemotherapy cycles/patient was 4 (range 3-8 cycles) and 6.5 (range 5-11) in group A and B patients, respectively. A reduction in systemic toxicity, statistically significant for neutropenia, associated with better results in term of OR rate, ICR, and BR were observed in group B compared with group A. On the contrary no significant difference in OS and PFS was detected between groups.
Conclusions: our study suggests that the use of ellagic acid as support therapy reduces chemotherapy induced toxicity, in particular neutropenia, in HRCP patients; however, further studies are required to confirm our results.
在这个临床试验里，鞣花酸的用法是 After reviewing the literature,a daily dose of 180 mg (60 mg/every 8 h) active principle wasselected and administered orally before meals with water (200–250 ml) throughout the chemotherapy cycles and during the period between cycles.
这个剂量比保健品的剂量还低，耐受应该没什么问题，直接买保健品吃就行了。

三、p53的R273C突变
1、p53的R273C突变会提高Axl的表达，因此要抑制Axl
《Gain-of-Function Activity of Mutant p53 in Lung Cancer through Up-Regulation of Receptor Protein Tyrosine Kinase Axl》
p53 mutations are present in up to 70% of lung cancer. Cancer cells with p53 mutations, in general, grow more aggressively than those with wild-type p53 or no p53. Expression of tumor-derived mutant p53 in cells leads to up-regulated expression of genes that may affect cell growth and oncogenesis. In our study of this aggressive phenotype, we have investigated the receptor protein tyrosine kinase Axl, which is up-regulated by p53 mutants at both RNA and protein levels in H1299 lung cancer cells expressing mutants p53-R175H, -R273H, and -D281G. Knockdown of endogenous mutant p53 levels in human lung cancer cells H1048 (p53-R273C) and H1437 (p53-R267P) led to a reduction in the level of Axl as well. This effect on Axl expression is refractory to the mutations at positions 22 and 23 of p53, suggesting that p53's transactivation domain may not play a critical role in the up-regulation of Axl gene expression. Chromatin immunoprecipitation (ChIP) assays carried out with acetylated histone antibodies demonstrated induced histone acetylation on the Axl promoter region by mutant p53. Direct mutant p53 nucleation on the Axl promoter was demonstrated by ChIP assays using antibodies against p53. The Axl promoter has a p53/p63 binding site, which however is not required for mutant p53-mediated transactivation. Knockdown of Axl by Axl-specific RNAi caused a reduction of gain-of-function (GOF) activities, reducing the cell growth rate and motility rate in lung cancer cells expressing mutant p53. This indicates that for lung cancer cell lines with mutant p53, GOF activities are mediated in part through Axl.
2、青蒿琥酯抑制Axl；青蒿琥酯分子量小；青蒿琥酯还抑制AKT
《青蒿琥酯对肺腺癌PC9细胞中Axl及其下游信号分子的影响》
“可见青蒿琥酯作用48 h后PC9 细胞内Axl、Akt、p - Axl、p - Akt蛋白的表达较对照组均有不同程度的降低, 且以p - Axl和p- Akt降低更为明显 ( 见图4) 。”
青蒿琥酯分子量 384.43，分子量很小，入脑好。
青蒿琥酯还抑制akt；患者有pten 突变要抑制akt；用青蒿琥酯一举两得。
3、《Long-term add-on therapy (compassionate use) with oral artesunate in patients with metastatic breast cancer after participating in a phase I study (ARTIC M33/2)》这篇论文讲了一个长期大剂量口服青蒿琥酯治疗乳腺癌的临床试验。
Methods: Patients continued to take 100, 150 or 200 mg oral ART daily as add-on therapy to their guideline-based oncological therapy. Clinical and laboratory monitoring included audiological and neurological examination, ECG, NTproBNP and reticulocyte determination. Cumulative treatment days and cumulative ART doses encompass both the phase I study as well as the continued add-on treatment period (CU).
Results: Following the 4 ± 1 weeks of the phase I trial, thirteen patients continued the add-on therapy as CU, resulting in a total of 3825 treatment days. In individual patients up to 1115 cumulative treatment days (37 months) and cumulative ART doses up to 167.3 g were reached. A total of 25 AEs grade ≥ 2 at least possibly related to ART long-term add-on therapy were documented, two, six and 17 in dose groups 100, 150 and 200 mg/d ART respectively. Six of these AEs were classified as grade 3, two in patients taking 150 and four in patients on 200 mg/d, none of them being probably or certainly related to ART.
Conclusions: In thirteen patients with metastatic breast cancer up to 200 mg/d long-term oral ART (2.3-4.1 mg/kg BW/d) in up to 1115 cumulative treatment days (37 months) did not result in any major safety concerns.
Keywords: Anti-malarial drug; Artesunate add-on therapy; Compassionate use; Long-term treatment; Metastatic breast cancer; Safety.
可以参考这个临床试验的用法，根据患者个体情况来。

四、pik3ca突变与pten突变
Pik3ca突变与pten突变要抑制akt，可以木犀草素这个akt抑制剂替代药物。
《In silico drug design and molecular docking studies targeting Akt1 (RAC-alpha serine/threonine-protein kinase) and Akt2 (RAC-beta serine/threonine-protein kinase) proteins and investigation of CYP (cytochrome P450) inhibitors against MAOB (monoamine oxidase B) for OSCC (oral squamous cell carcinoma) treatment》
木犀草素与akt1的 Binding Affinity 是 -12.3 kcal/mol，与akt2的 Binding Affinity 是 -11.4 kcal/mol，卡帕塞替尼与akt1的 Binding Affinity 是 -10.3 kcal/mol。
当然，因为植物素成药的通病，生物利用度太低，代谢时间太短，实际药效肯定是很弱的。木犀草素一定要跟伽马环糊精做成纳米脂质体乳化剂吃才行。