KR20230170695A - Methods of treating lung cancer and non-small cell lung cancer - Google Patents

Abstract

A method of treating NSCLC or lung cancer in a subject comprising administering to the subject an effective amount of a composition comprising nanomolar potency particles comprising acylfulvene. The treatment may be based on an individual suffering from squamous cell carcinoma.

Description

Methods of treating lung cancer and non-small cell lung cancer

Cross-reference to related applications

This application claims priority from U.S. Provisional Patent Application No. 63/173,968, filed April 12, 2021, the contents of which are incorporated herein by reference in their entirety.

Technology field

This application relates to methods of treating cancer, particularly lung cancer. The present application also relates to methods and compositions for treating non-small cell lung cancer (NSCLC) and lung cancer by administering compositions comprising nanomolar potency of acylfulvene.

Lung cancer remains the most common cause of cancer-related death. This applies to both men and women. In 2020, lung cancer caused more deaths in the United States than breast, prostate, colon, and brain cancer.

Most lung cancer caused by smoking is non-small cell lung cancer (NSCLC), which accounts for approximately 90% of all lung cancers. There are three main types of NSCLC: squamous cell carcinoma, large cell carcinoma, and adenocarcinoma. Adenocarcinoma is the most common form of lung cancer and is the most commonly found lung cancer in both smokers and non-smokers. Squamous cell carcinoma is usually found in the proximal bronchi. Early stage NSCLC tends to be localized and, if detected early, can often be treated surgically with good outcomes and improved survival. Other treatment options include radiation therapy, drug therapy, and combinations of these methods.

The stage of NSCLC is determined by the size of the tumor and the presence of tumor in other tissues, including lymph nodes. In the occult stage, cancer cells are found in sputum or lavage samples and no tumors are found in the lungs. In stage 0, cancer cells appear only in the innermost lining of the lung and the tumor does not grow through the lining. In stage IA, the cancer is considered invasive and has grown deep into the lung tissue, but the tumor is less than 3 cm in size. In this stage, no tumors are found in the bronchi or lymph nodes. In stage IB, the tumor is larger than 3 cm in diameter or has grown into the bronchial tubes or pleura, but has not grown into the lymph nodes. In stage IIA, the tumor was larger than 3 cm and had grown into the lymph nodes. In stage IIB, the tumor is found in the lymph nodes and is greater than 3 cm in diameter or has grown into the bronchi or pleura, or the cancer is not found in the lymph nodes but in the chest wall, diaphragm, pleura, bronchi, or tissues surrounding the heart. . In stage IIIA, cancer cells are found in the lymph nodes near the lungs and bronchial tubes and in the lymph nodes between the lungs but on the side of the chest where the tumor is located. In stage IIIB, cancer cells are located in the chest and neck opposite the tumor. Cancer cells may also be present in other organs near the lungs, and multiple tumors may be found in one lobe of the lung. In stage IV, tumors are found in more than one lobe of the same lung or in both lungs and cancer cells are found in other parts of the body. Cancer must be treated in all stages.

Therefore, there is always a need for treatments for non-small cell lung cancer (NSCLC) and lung cancer.

This application discloses methods of treating lung cancer and NSCLC in an individual. The method includes administering to a subject an effective amount of a composition comprising nanomolar potency particles comprising acylfulvene.

Another aspect includes compositions (e.g., pharmaceutical compositions), medicines, kits, and unit dosages useful in the methods described herein.

Another embodiment of the present application is to mix an effective amount of hydroxyureamethyl-acylfulvene with an effective amount of temozolomide, bevacizumab, everolimus, carmustine, lomustine, procarbazine, vincristine, irinotecan, cisplatin. , carboplatin, methotrexate, etoposide, vinblastine, bleomycin, actinomycin, cyclophosphamide, and ifosfamide, for the treatment of lung cancer and NSCLC. Includes how to do it.

Another aspect herein includes a method of treating lung cancer and NSCLC using an effective amount of hydroxyureamethyl-acylfulvene in combination with radiation therapy. The radiation therapy may be selected from lung irradiation, fractionated radiation therapy, radiosurgery, and combinations thereof. Radiation may be applied before, during, or after treatment with an effective dose of hydroxyureamethyl-acylfulvene.

Another aspect herein includes methods where the patient is a human or animal.

Figure 1 shows that hydroxyureamethyl-acylfulvene exhibits nanomolar potency in various NSCLC cell lines.
Figure 2 shows hydroxyureamethyl-acylfulvene sensitivity and PTGR1 transcript levels on the X-axis across 19 NSCLC cell lines.
Figure 3 shows hydroxyureamethyl-acylfulvene potency in terms of nanomolar IC50 compared between oxariplatin, cisplatin, pemetrexed, paclitaxel and gemcitabine from the GDSC database.
Figure 4 shows brain metastasis model LXFE 2478 derived from primary lung cancer in terms of nanomolar IC50 (Y-axis) of hydroxyureamethyl-acylfulvene compared to erlotinib, gefitinib and osimertinib. It shows nanomolar effect.
Figure 5 shows results from the H460 nude mouse xenograft model administered intraperitoneally with hydroxyureamethyl-acylfulvene on the dates indicated by arrows on the x-axis (N=10 per group).
Figure 6 shows that the values adjacent to highly-mutated genes are permutation test p-values of PTGR1 relative gene expression between driver mutated samples (black) and non-mutated samples (white).
order
SEQ ID NO: 1 - amino acid sequence of PTGR1,
SEQ ID NO: 2 - amino acid sequence of KEAP1,
SEQ ID NO: 3 - amino acid sequence of KRAS,
SEQ ID NO: 4 - amino acid sequence of TP53, and
SEQ ID NO: 5 - Amino acid sequence of STK11.
Justice
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a person skilled in the art to which the subject matter pertains. As used herein, the following definitions are provided to facilitate understanding of the invention.
The amino acid sequence shown in SEQ ID NO: or, when compared to the amino acid sequence set forth in SEQ ID NO: means that the variant amino acid sequence and the amino acid sequence set forth in SEQ ID NO:
The term “based on” includes assessing, determining or measuring patient characteristics (and preferably selecting appropriate patients to receive treatment) as described herein.
The term “simultaneous administration” means that in combination therapy, the administration of the first-line treatment and the administration of the second-line treatment overlap each other.
As used herein, the term “effective amount” means an amount of a compound or composition sufficient to treat a particular disorder, condition or disease, e.g., sufficient to improve, alleviate, alleviate and/or delay one or more of its symptoms. . With respect to NSCLC, an effective amount includes an amount sufficient to shrink a tumor and/or reduce the rate of tumor growth (e.g., inhibit tumor growth) or prevent or delay other unwanted cell proliferation in NSCLC. do. In some embodiments, the effective amount is an amount sufficient to delay the development of NSCLC. In some embodiments, the effective amount is an amount sufficient to prevent or delay recurrence. An effective amount may be administered in one or more administrations. For NSCLC, an effective amount of a drug or composition will: (i) reduce the number of NSCLC cells; (ii) reduce tumor size; (iii) inhibit, delay, slow to some extent, and/or preferably stop NSCLC cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent, and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay the development and/or recurrence of tumors; (vii) may alleviate to some extent one or more of the symptoms associated with NSCLC.
The term “healthy subject” should be considered to mean an subject not known to have cancer (e.g., lung cancer or NSCLC), for which information is available, including but not limited to diagnostic assays other than those described herein. , obtained from clinical data on the subject.
“Baseline level” means a level of a compound of the invention or additional biomarker(s) that is indicative of a particular disease state, phenotype, or lack thereof, as well as a combination of disease states, phenotypes, or lack thereof.
“Reference sample” means a sample containing a reference level of a biomarker. For example, a reference sample may be obtained from a subject who does not have a particular disease, disease state, or phenotype, such as cancer or acute injury.
As used herein, “likely to respond” or “responsiveness” means measurable reduction in tumor size or evidence of disease or disease progression, complete response, partial response, stable disease, increase or prolongation of progression-free survival. means an improvement or positive response of any kind, clinical or non-clinical, selected from, but not limited to, increased or prolonged overall survival.
The terms “lung tissue” and “lung cancer” refer, respectively, to tissue or cancer of the lung itself, as well as tissue adjacent to and/or within the layers underlying the lung and supporting structures, such as the pleura, intercostal muscles, ribs, and other elements of the respiratory system. It means tissue or cancer. In this context, the respiratory system itself consists of the nasal cavity, paranasal sinuses, pharynx, larynx, trachea, bronchi, lungs, lobes, alveoli, alveolar ducts, alveolar sacs, alveolar capillaries, bronchioles, respiratory bronchioles, visceral pleura, parietal pleura, pleural cavity, diaphragm, It is considered to represent the epiglottis, adenoids, tonsils, mouth, and tongue. The tissue or cancer may be of mammalian origin, preferably of human origin, but is also within the scope of the present invention if it is derived from monkeys, apes, cats, dogs, cows, horses and rabbits. As used herein, the term “lung disease” refers to a disease, event, or health condition change associated with the lungs, including, for example, lung cancer and various non-cancerous diseases.
When applied to polypeptides, the term "substantial similarity" or "substantially similar" means that two peptide sequences, when optimally aligned, for example by the programs GAP or BESTFIT using the default gap weight, This means sharing at least 95% sequence identity, more preferably at least 98% or 99% sequence identity. Preferably, residue positions that are not identical differ by conservative amino acid substitutions. A “conservative amino acid substitution” is one in which an amino acid residue is replaced by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). In general, conservative amino acid substitutions do not substantially change the functional properties of the protein. When two or more amino acid sequences differ from each other by conservative substitution, the conservative nature of the substitution can be adjusted by adjusting the percent sequence identity or degree of similarity upward. Means for such adjustments are well known to those skilled in the art. See, for example, Pearson (1994) Methods Mol. Biol.24: 307-331]. Examples of groups of amino acids with side chains with similar chemical properties include (1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; (2) Aliphatic-hydroxyl side chains: serine and threonine; (3) Amide-containing side chains: asparagine and glutamine; (4) Aromatic side chains: phenylalanine, tyrosine, and tryptophan; (5) base side chains: lysine, arginine and histidine; (6) acid side chains: aspartate and glutamate, (7) sulfur-containing side chains: cysteine and methionine. Preferred conservative amino acid substitution groups are valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamate-aspartate and asparagine-glutamine. Alternatively, conservative substitutions can be made as described in Gonnet et al. (1992) Science 256: 1443-1445] is a positive arbitrary change in the PAM250 log-likelihood matrix. A “medium conservative” permutation is any change that has non-negative values in the PAM250 log-likelihood matrix.
The term “treatment” or “treating” refers to an approach to achieve a beneficial or desired result, including clinical outcome. For the purposes of the present invention, a beneficial or desired clinical outcome includes, but is not limited to, one or more of the following: alleviation of one or more symptoms due to the disease, reduction of the extent of the disease, stabilization of the disease (e.g., prevention of worsening of the disease), prevention or delay), prevention or delay of the spread (e.g. metastasis) of the disease, prevention or delay of recurrence of the disease, delay or slowing of the progression of the disease, improvement of the disease state, or remission (partial or full) of the disease. Providing, reducing the dose of one or more other medications needed to treat the disease, delaying disease progression, improving quality of life, and/or prolonging survival. “Treatment” also includes reduction of the pathological consequences of NSCLC or lung cancer. The methods of the present invention contemplate one or more of these treatment modalities.
The term “therapeutic effect” refers to a beneficial local or systemic effect in animals, particularly mammals, and more particularly humans, resulting from administration of a compound or composition of the invention. The phrase “therapeutically effective amount” means an amount of a compound or composition of the invention effective to treat a disease or condition resulting from abnormal biological activity with a reasonable benefit/risk ratio. In some embodiments, the therapeutically effective amount of hydroxyureamethyl-acylfulvene or a pharmaceutically acceptable salt thereof is 0.5 mg/day, 1 mg/day, 2.5 mg/day, 5 mg/day, 10 mg/day, 20 mg/day. mg/day, 30 mg/day, 60 mg/day, 90 mg/day, 120 mg/day, 150 mg/day, 180 mg/day, 210 mg/day, 240 mg/day, 270 mg/day, 300 mg/day, 360 mg/day, 400 mg/day, 440 mg/day, 480 mg/day, 520 mg/day, 580 mg/day, 600 mg/day, 620 mg/day, 640 mg/day, 680 mg/day and 720 mg/day.

Disclosed herein are methods of treating non-small cell lung cancer (NSCLC) and lung cancer in an individual in need thereof, comprising administering to the individual a composition comprising an effective amount of nanomolar potency acylfulvene.

One embodiment is a method of treating a patient with lung cancer and/or non-small cell lung carcinoma, comprising administering to the patient with lung cancer or non-small cell lung carcinoma a therapeutically effective amount of hydroxyureamethyl acylfulvene or thereof. It includes a method of administering salt.

Hydroxyureamethyl acylfulvene or hydroxyureamethyl-acylfulvene (now named LP-184 by Lantern Pharma, Inc.) is a semisynthetic or synthetic antineoplastic agent derived from the mushroom toxin Iludin S. The structure of each isomer is as follows.

Certain embodiments are applicable to various histological types of NSCLC. NSCLC is defined as squamous cell carcinoma (i.e., epidermoid carcinoma), large cell carcinoma, adenocarcinoma, adenosquamous carcinoma, carcinoma with pleomorphic, sarcomatoid, or sarcomatous elements, carcinoid tumor, or salivary gland tumor. It could be cancer. In some embodiments, the NSCLC is squamous cell carcinoma. In some embodiments, the squamous cell carcinoma is papillary, clear cell, small cell, or basaloid. In some embodiments, the NSCLC is adenocarcinoma. In some embodiments, the adenocarcinoma is an adenocarcinoma, papillary carcinoma, bronchioloalveolar carcinoma (e.g., nonmucinous, mucinous, mixed mucinous, and nonmucinous or indeterminate cell type), solid adenocarcinoma with mucin, mixed subtype. adenocarcinoma, well-differentiated fetal adenocarcinoma, mucinous (colloid) adenocarcinoma, mucinous cystadenocarcinoma, signet ring adenocarcinoma, or clear cell adenocarcinoma. In some embodiments, the large cell carcinoma is large cell neuroendocrine carcinoma, complex large cell neuroendocrine carcinoma, basaloid carcinoma, lymphoepithelioma-like carcinoma, clear cell carcinoma, or large cell carcinoma with a rhabdoid phenotype. . In some embodiments, the carcinoma with pleomorphic, sarcomatous, or sarcomatous elements is carcinoma with spindle and/or giant cells, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, or pulmonary blastoma. In some embodiments, the salivary gland type carcinoma is mucoepidermoid carcinoma or adenoid cystic carcinoma. In one example, hydroxyureamethyl acylfulvene or its salt may be administered before, with, or after the administration of a chemotherapy agent or chemotherapy agents. [0041] NSCLC of any of the methods herein may be an occult tumor, a stage 0 tumor, a stage I tumor (stage IA (T1, N0, M0) or stage IB (T2, N0, M0)), a stage II tumor (stage IIA ( Stage IIIA tumor (T1, N1, M0) and IIB (T2, N1, M0)), Stage IIIA tumor (T1, N2, M0, T2, N2, M0, T3, N1, M0 or T3, N2, M0), Stage IIIB tumor (any T, N3, M0 or T4, any N, M0) or stage IV tumor (any T, any N, M1). In some embodiments of any of the methods described herein, the NSCLC is early stage NSCLC, non-metastatic NSCLC, primary NSCLC, advanced NSCLC, locally advanced NSCLC, metastatic NSCLC, remitted NSCLC, or relapsed NSCLC. In some embodiments, the NSCLC is locally resectable, locally unresectable, or unresectable. In some embodiments, the NSCLC is unresectable Stage IV NSCLC. In some embodiments, the NSCLC is inoperable stage IIIA and/or stage IIIB NSCLC, PS 0-1 and FEV 1 > 800 ml.

In another embodiment, any of the above treatment methods comprises the additional step of co-administering one or more second therapeutic agents to the patient. The choice of combination of agent or second therapeutic agent can be made from any second therapeutic agent known to be useful for co-administration with hydroxyureamethyl acylfulvene or its salt. The choice of second therapeutic agent also depends on the specific disease or condition being treated. Examples of second therapeutic agents that can be used in the methods of the present application are those presented above for use in combination compositions comprising a compound of the invention and a second therapeutic agent.

In another embodiment, the second therapeutic agent is a camptothecin derivative, paclitaxel, docetaxel, epothilone B, 5-FU, gemcitabine, oxariplatin, cisplatinum, carboplatin, melphalam, dacarbazine, temozolomide. , doxorubicin, imatinib, erlotinib, bevacizumab, cetuximab, and Raf kinase inhibitors.

In another embodiment, the second therapeutic agent is one or more chemotherapy agents selected from paclitaxel or cisplatinum.

Some embodiments include the steps of: (1) performing a physical examination of a patient; (2) using magnetic resonance imaging (“MRI”) to determine whether the patient has a tumor in the lung; (3) performing a lung biopsy to obtain genetic information about the cancer, including molecular subtype and genetic signature; and (4) prescribing effective treatment of hydroxyureamethyl-acylfulvene to the subject suffering from lung cancer or NSCLC.

Another embodiment includes detecting the presence of specific genetic information in a human subject; A method of treating lung cancer or NSCLC comprising administering hydroxyureamethyl-acylfulvene or a pharmaceutically acceptable salt thereof to the human subject when the subject overexpresses or underexpresses a specific marker. The marker may be substantially similar to PTGR1 (SEQ ID NO: 1), KEAP1 (SEQ ID NO: 2), KRAS (SEQ ID NO: 3), TP53 (SEQ ID NO: 4) and STK11 (SEQ ID NO: 5).

Another embodiment includes (a) obtaining or obtaining expression levels for a plurality of targets in a sample from a subject, wherein the plurality of targets include PTGR1 (SEQ ID NO: 1) and KEAP1, KRAS, TP53, and STK11 A step comprising a group consisting of one or more of the following; (b) determining whether the subject is susceptible to treatment with hydroxyureamethyl-acylfulvene; and (c) administering a cancer treatment agent comprising hydroxyureamethyl-acylfulvene.

The duration of administration may be a multi-week treatment cycle, as long as the tumor is under control and the therapy is clinically acceptable. In some embodiments, a single dose of hydroxyureamethyl-acylfulvene or other therapeutic agent is administered once a week, preferably once each on days 1 and 8 of a 3-week (21-day) treatment cycle. You can. In some embodiments, a single dose of hydroxyureamethyl-acylfulvene or other therapeutic agent is administered once per week, twice per week, three times per week, or per week for a 1, 2, 3, 4, or 5 week treatment cycle. It may be administered 4 times, 5 times a week, 6 times a week, or daily. Administration may occur on the same or different days of each week in the treatment cycle.

Protein sequences of specific proteins identified herein include PTGR1 (SEQ ID NO: 1), KEAP1 (SEQ ID NO: 2), KRAS (SEQ ID NO: 3), TP53 (SEQ ID NO: 4), and STK11 (SEQ ID NO: 5).

The therapeutically effective dose will depend, as will be appreciated by those skilled in the art, on the disease being treated, the severity of the disease, the route of administration, the age and general health of the patient, the use of excipients, the possibility of combination with other treatments, such as the possibility of use of other medications, and It may vary depending on the judgment of the treating doctor. For example, guidance on selecting an effective dose can be determined by reference to the prescribing information for hydroxyureamethyl acylfulvene or the discussion in the literature.

The hydroxyureamethyl-acylfulvene used according to the invention is mainly administered parenterally, specifically such as subcutaneously, intramuscularly, intravenously, transdermally, intrathecally, epidurally, intraarticularly and topically. It may be administered by administration, or it may be administered in various dosage forms, for example by oral administration, if possible.

Injectable preparations for administration include, for example, sterile, aqueous or non-aqueous solutions, suspensions and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Non-aqueous solutions and suspensions include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (trade name). These compositions may contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersing agents, stabilizers (e.g. lactose) and solubilizing agents (e.g. meglumine). They are sterilized by filtration through bacteria-inhibiting filters, mixing with disinfectants, or irradiation. Alternatively, they may be produced as sterile solid compositions and then dissolved or suspended in sterile water for injection or a sterile solvent prior to use.

Dosage ranges for administration of agents according to the methods described herein may vary depending on, for example, the form of the agent, its potency, and the degree to which symptoms, markers or indicators of the conditions described herein are desired to be reduced, e.g., tumor growth. Depends on the desired reduction ratio for . The dosage should not be so high that it causes side effects. In general, the dosage will vary depending on the age, condition and gender of the patient and can be determined by one skilled in the art. If complications occur, the individual doctor may adjust the dosage.

The efficacy of an agent described herein, e.g., in the treatment of a condition described herein or intended to induce a response described herein (e.g., lung cancer), can be determined by a skilled clinician. However, after treatment according to the methods described herein, one or more signs or symptoms of the conditions described herein are altered in a favorable manner, or other clinically acceptable symptoms are improved or even alleviated, or the desired response is achieved, for example by at least 10%. % induction, the treatment is considered “effective treatment” (as this term is used herein). Efficacy can be determined, for example, by measuring markers, indicators, symptoms and/or incidence of the condition being treated according to the methods described herein or any other measurable suitable parameter, such as tumor size and/or growth rate. can be evaluated. Efficacy may also be measured by the individual being free from worsening resulting in hospitalization or need for medical intervention (i.e., progression of the disease is halted). Methods for measuring these indicators are known to those skilled in the art and/or described herein. Treatment includes any treatment of a disease in an individual or animal (some non-limiting examples include humans or animals), including (1) suppressing the disease, such as worsening symptoms (e.g., pain or inflammation); ) to prevent; or (2) lessening the severity of the disease (e.g., causing symptom regression). An effective amount for the treatment of a disease means an amount sufficient to, when administered to a subject in need thereof, result in effective treatment as that term is defined herein for the disease in question. The efficacy of an agent can be determined by assessing physical indicators of the condition or desired response. It is within the ability of those skilled in the art to monitor the efficacy of administration and/or treatment by measuring any one or any combination of these parameters. Efficacy can be assessed in animal models of the conditions described herein, such as in the treatment of lung cancer in mouse models. When using experimental animal models, treatment efficacy is demonstrated when statistically significant changes are observed in parameters such as tumor size and/or growth rate. In some embodiments, the therapeutically effective amount of hydroxyureamethyl-acylfulvene or a pharmaceutically acceptable salt thereof is 0.5 mg/day, 1 mg/day, 2.5 mg/day, 5 mg/day, 10 mg/day, 20 mg/day. mg/day, 30 mg/day, 60 mg/day, 90 mg/day, 120 mg/day, 150 mg/day, 180 mg/day, 210 mg/day, 240 mg/day, 270 mg/day, 300 mg/day, 360 mg/day, 400 mg/day, 440 mg/day, 480 mg/day, 520 mg/day, 580 mg/day, 600 mg/day, 620 mg/day, 640 mg/day, 680 mg/day and 720 mg/day.

The methods described herein are useful in various aspects of treating lung cancer or NSCLC. In some embodiments of any of the methods, the method comprises the step of a) administering to the individual an effective amount of a composition comprising particles comprising hydroxyureamethyl-acylfulvene, wherein the method inhibits NSCLC cell proliferation (e.g., NSCLC tumor) in the individual. Includes methods of inhibiting growth. In some embodiments, cell proliferation is inhibited by at least about 10% (e.g., including any of at least about 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 100%). .

In some embodiments of any of the methods described herein, the treatment method results in an objective response (eg, a partial response or a complete response).

In some embodiments of any of the methods described herein, the treatment method improves quality of life.

The specific dosage and treatment regimen for any particular patient will depend on the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the specific disease being treated. It should also be understood that it will depend on a variety of factors, including the severity of the condition. The amount of a compound of the invention in the composition will also vary depending on the particular compound in the composition. It may be advisable to administer the highest tolerable dose.

Treatment may include the use of one or more biomarkers. A biomarker may be lower, higher, or equal to the level of that marker in a healthy person. In one example, upregulation of the following genes may be associated with increased sensitivity to hydroxyureamethyl-acylfulvene: CD55, GLIS3, PRKCDBP, EGF, GLRX, SLC16A7, ABLIM3, DUSP4, ABCG2, HSPB8, TSPAN8, FKBP7, RGS2, CCPG1, DDIT4L, CTSL, PMP22, ACS33, HYAL1, KRT83, SLC16A14, AKR1B10, CA12, SDC2, HHIPL2, MCTP1.

In some embodiments, the expression level measures the expression level of a gene of interest for a given patient population, determines the median expression level of that gene for that population, and compares the expression level of the same gene for a single patient to a given patient population. It is determined by comparing to the median expression level of . For example, if the expression level of the gene of interest for the single patient is determined to be higher than the median expression level of the patient population, then that patient is determined to have a high expression level of the gene of interest. Alternatively, if the expression level of the gene of interest for a single patient is determined to be lower than the median expression level of the patient population, then that patient is determined to have a low expression level of the gene of interest. In some embodiments, the single patient has NSCLC and the patient population does not have cancer (i.e., is normal). In some embodiments, the single patient has one histologic type of NSCLC (e.g., squamous cell carcinoma) and the population of patients has a second histologic type of NSCLC (e.g., adenocarcinoma). there is. In some embodiments, the single patient and the population of patients have the same histological type of NSCLC (eg, squamous cell carcinoma).

This method of determining expression levels is not limited to the technique used to determine the expression level of the gene of interest. Nucleic acid (e.g., RNA or DNA) or protein levels of the gene of interest can be measured. Methods for measuring gene expression and/or determining sequences for polymorphism detection are well known in the art and include immunological assays, nuclease protection assays, northern blots, in situ hybridization, and ELISA. , reverse transcriptase polymerase chain reaction (RT-PCR), real-time polymerase chain reaction, expressed sequence tag (EST) sequencing, cDNA microarray hybridization or gene chip analysis, subtractive cloning, serial analysis of gene expression (SAGE), Includes, but is not limited to, massively parallel signature sequencing (MPSS) and sequencing by synthesis (SBS). Diagnostic procedures may also be performed directly in the field on tissue sections (fixed and/or frozen) of patient tissue obtained from biopsy or resection.

Examples and Results

Example 1

Nineteen human NSCLC cell lines were treated with hydroxyureamethyl-acylfulvene in a 96 well format in triplicate over concentrations ranging from 14 nM to 10 μM. Treatment was conducted for 72 hours, and cell viability was analyzed using Promega's CellTiter Fluor reagent. As shown in Figure 1, drug sensitivity was measured in terms of IC50 values generated from dose response curves plotted in GraphPad Prism. Representative dose response curves are not shown. Overall, LP_184 demonstrated strong nanomolar potency in most NSCLC cell lines tested, indicating broad antitumor cytotoxicity in this panel. In these 19 NSCLC cell lines, the IC50 ranged from 45 to 1805 nM, the median IC50 was 371 nM, and the average IC50 was 571 nM.

Example 2

These studies of the hydroxyureamethyl-acylfulvene response in primary NSCLC cell lines were extended to an in vitro model of brain metastases originating from primary lung cancer. These two models LXFA 983 and LXFE 2478 were tested for sensitivity to hydroxyureamethyl-acylfulvene in both 2D and 3D culture systems. For 2D cultures, the CellTiter-Glo® assay provided a cell viability readout, while for 3D cultures, the 3D Clonogenic assay provided the essential stain-based colony formation readout. As shown in Figure 4, hydroxyureamethyl-acylfulvene retained efficacy in this model with an IC50 ranging from 88 nM to 3209 nM.

These results highlight the translational relevance of hydroxyurea methyl-acylfulvene due to its blood-brain barrier crossing properties.

As shown in Figure 2, hydroxyureamethyl-acylfulvene sensitivity was found to be correlated with PTGR1 transcript levels in the tested NSCLC cell lines (Pearson Correlation Coefficient r = -0.603, p value 6.076 E-05). Using an average hydroxyureamethyl-acylfulvene IC50 value of 571 nM, NSCLC cell lines were divided into high-sensitivity and low-sensitivity groups. PTGR1 expression was compared in two groups of NSCLC cell lines tested: 11 cell lines with hydroxyureamethyl-acylfulvene IC50 <571 nM and 8 cell lines with IC50 >571 nM.

To investigate the impact of KEAP1 mutations on PTGR1 transcription levels in the panel of 19 NSCLC cell lines tested, PTGR1 expression was determined between two groups of cell lines: 7 cell lines with KEAP1 mutations and 12 cell lines without KEAP1 mutations. compared. The present inventors confirmed that the difference in PTGR1 expression between KEAP1 mutant and wild-type cell lines was significant in one-tailed t-test analysis (p value 0.0253). In comparison, PTGR1 expression is completely independent of mutations in KRAS, TP53, and STK11 (which are commonly altered in NSCLC but currently have no effective targeted treatment options).

Example 3

An extensive comparison in selected NSCLC cell lines was performed using the hydroxyureamethyl-acylfulvene reaction with previously published reactions of commonly prescribed standard chemotherapy agents obtained from the GDSC database. In particular, there were oxariplatin and cisplatin that also acted as DNA alkylating agents, probably through mechanisms that did not overlap with those recognized for hydroxyureamethyl-acylfulvene. Known responses have been obtained with the antimetabolites pemetrexed and gemcitabine, which are currently considered standard treatment options for NSCLC. Lung adenocarcinoma can also be treated with taxanes. Publicly available IC50 data for oxariplatin, cisplatin, pemetrexed, paclitaxel, and gemcitamine were collected after 72 hours of treatment, as was hydroxyureamethyl acylfulvene, and typically, data reported as means without standard errors. Obtained from the GDSC database. In this relative cytotoxicity assay on selected NSCLC cell lines, as shown in Figure 3, hydroxyureamethyl-acylfulvene was found to be up to 3,800 times more potent than some of these chemotherapy agents approved for medical use in NSCLC. .

Example 4

The brain metastasis model LXFE 2478 carries a heterozygous EGFR-activating mutation, an EGFR exon 20 insertion (M766_A767insASV). Patients deriving this model have been reported to be resistant to radiotherapy, cisplatin/erlotinib/pemetrexed combination therapy, and PD-L1 antibody treatment. In this model, the published in vitro 2D efficacy of various EGFR inhibitors was compared to that of hydroxyureamethyl-acylfulvene under similar conditions, demonstrating that hydroxyureamethyl-acylfulvene is effective against the early generation EGFR inhibitors erlotinib and gefitinib. It was confirmed that hydroxyureamethyl-acylfulvene was located within this spectrum, being about 6 times more potent than the latest generation EGFR inhibitor osimertinib and about 2.4 times less potent than the latest generation EGFR inhibitor osimertinib (Figure 4).

Example 5

Hydroxyureamethyl-acylfulvene antitumor response was assessed in vivo in the NCI-H460 lung tumor model as subcutaneous xenografts in nude mice. Ten mice were included in vehicle control and treatment groups. As shown in Figure 5, hydroxyureamethyl-acylfulvene treatment was performed using a 5 mg/kg injection regimen administered intraperitoneally on days 1, 3, 6, 9, and 12. Individual mouse tumor volumes and body weights at sampling date are not shown. This treatment resulted in a statistically significant difference in mean tumor volume between the vehicle control and treatment groups on days 8, 12, and 15. Therefore, hydroxyureamethyl-acylfulvene demonstrated antitumor efficacy in a lung cancer model.

Example 6

We investigated the PTGR1 expression status in relation to the mutation status of multiple related genes in a clinical data set of NSCLC. After analyzing the records of 533 NSCLC adenocarcinoma patients from the TCGA portal, PTGR1 was found to be highly expressed in KEAP1 mutant samples. In the plot of Figure 6, the value adjacent to the highly-mutated gene is the permutation test p-value of PTGR1 relative gene expression between driver mutated samples (black) and non-mutated samples (white). This result is most statistically significant for KEAP1 (p value 0.00126), with PTGR1 being highly expressed in KEAP1 mutant samples. Within this PTGR1-high subset, a separate group was enriched in KEAP1, KRAS, BRAF, EGFR, NRF2, MET, and AKT1 mutations. The population with such mutations resulting in elevated PTGR1 levels potentially represents a molecularly defined subgroup of NSCLC patients who would benefit from hydroxyureamethyl-acylfulvene based therapy.

SEQ ID NO: 1 (PTGR1)

MVRTKTWTLKKHFVGYPTNSDFELKTAELPPLKNGEVLLEALFLTVDPYMR VAAKRLKEGDTMMGQQVAKVVESKNVALPKGTIVLASPGWTTHSISDGKDLEKLLTEWPDTIPLSLALGTVGMPGLTAYFGLLEICGVKGGETVMVNAAAGAVGSVVGQIAKLKGCKVVGAVGSDEKVAYLQKLGFDVVFNYKTVESLEETLKKA SPDGYDCYFDNVGGEFSNTVIGQMKKFGRIAICGAISTYNRTGPLPPGPPPEIVIYQELRMEAFVVYRWQGDARQKALKDLLKWVLEGKIQYKEYIIEGFENMPAAFMGMLKGDNLGKTIVKA

SEQ ID NO: 2 (KEAP1)

MQPDPRPSGAGACCRFLPLQSQCPEGAGDAVMYASTECKAEVTPSQHGNRTFSYTLEDHTKQAFGIMNELRLSQQLCDVTLQVKYQDAPAAQFMAHKVVLASSSPVFKAMFTNGLREQGMEVVSIEGIHPKVMERLIEFAYTASISMGEKCVLHVMNGAVMYQIDSVVRACSDFLVQQLDPSNAIGIANFAEQIGCVELHQR AREYIYMHFGEVAKQEEFFNLSHCQLVTLISRDDLNVRCESEVFHACINWVKYDCEQRRFYVQALLRAVRCHSLTPNFLQMQLQKCEILQSDSRCKDYLVKIFEELTLHKPTQVMPCRAPKVGRLIYTAGGYFRQSLSYLEAYNPSDGTWLRLADLQVPRSGLAGCVVGGLLYAVGGRNNSPDGNTDSSALDCYNPMTNQWSPCAPMSVP RNRIGVGVIDGHIYAVGGSHGCIHHNSVERYEPERDEWHLVAPMLTRRIGVGVAVLNRLLYAVGGFDGTNRLNSAECYYPERNEWRMITAMNTIRSGAGVCVLHNCIYAAGGYDGQDQLNSVERYDVETETWTFVAPMKHRRSALGITVHQGRIYVLGGYDGHTFLDSVECYDPDTDTWSEVTRMTSGRSGVGVAVTMEPCRKQIDQQNCTC

SEQ ID NO: 3 (KRAS)

MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSAKTRQRVEDAFYTLVREIRQYRLKKISKEEKTPGCVKIKKCIM

SEQ ID NO: 4 (TP53)

MEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPGPDEAPRMPEAAPPVAPAPAAPTPAAPAPAPSWPLSSSVPSQKTYQGSYGFRLGFLHSGTAKSVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCPHHERCSDSDGLAPPQHLIRVEGNLRVEYLDDRNTFRHSVVVP YEPPEVGSDCTTIHYNYMCNSSCMGGMNRRPILTIITLEDSSGNLLGRNSFEVRVCACPGRDRRTEEENLRKKGEPHHELPPGSTKRALPNNTSSSPQPKKKPLDGEYFTLQIRGRERFEMFRELNEALELKDAQAGKEPGGSRAHSSHLKSKKGQSTSRHKKLMFKTEGPD SD

SEQ ID NO: 5 (STK11)

MEVVDPQQLGMFTEGELMSVGMDTFIHRIDSTEVIYQPRRKRAKLIGKYLMGDLLGEGSYGKVKEVLDSETLCRRAVKILKKKKLRRIPNGEANVKKEIQLLRRLRHKNVIQLVDVLYNEEKQKMYMVMEYCVCGMQEMLDSVPEKRFPVCQAHGYFCQLIDGLEYLHSQGIVHKDIKPGNLLLTTGGTLKISDLGVAEAL HPFAADDTCRTSQGSPAFQPPEIANGLDTFSGFKVDIWSAGVTLYNITTGLYPFEGDNIYKLFENIGKGSYAIPGDCGPPLSDLLKGMLEYEPAKRFSIRQIRQHSWFRKKHPPAEAPVPIPPSPDTKDRWRSMTVVPYLEDLHGADEDEDLFDIEDDIIYTQDFTVPGQVPEEEASHNGQRRGLPKAVCMNGTEAAQLSTKSRAEGRAPNPARKACSASKACS IRRLSACKQQ

Although the foregoing invention has been described in some detail by way of examples and examples for clarity of understanding, it will be apparent to those skilled in the art that certain minor changes and modifications may be practiced. Therefore, the detailed description and examples should not be construed as limiting the scope of the present invention.

SEQUENCE LISTING <110> LANTERN PHARMA INC. <120> METHOD FOR TREATING LUNG CANCER AND NON-SMALL CELL LUNG CANCER <130> 197585-010421 <140> PCT/US2022/071676 <141> 2022-04-12 <150> US 63/173,968 <151> 2021-04 -12 <160> 5 <170> PatentIn version 3.5 <210> 1 <211> 329 <212> PRT <213> Homo sapiens <400> 1 Met Val Arg Thr Lys Thr Trp Thr Leu Lys Lys His Phe Val Gly Tyr 1 5 10 15 Pro Thr Asn Ser Asp Phe Glu Leu Lys Thr Ala Glu Leu Pro Pro Leu 20 25 30 Lys Asn Gly Glu Val Leu Leu Glu Ala Leu Phe Leu Thr Val Asp Pro 35 40 45 Tyr Met Arg Val Ala Ala Lys Arg Leu Lys Glu Gly Asp Thr Met Met 50 55 60 Gly Gln Gln Val Ala Lys Val Val Glu Ser Lys Asn Val Ala Leu Pro 65 70 75 80 Lys Gly Thr Ile Val Leu Ala Ser Pro Gly Trp Thr Thr His Ser Ile 85 90 95 Ser Asp Gly Lys Asp Leu Glu Lys Leu Leu Thr Glu Trp Pro Asp Thr 100 105 110 Ile Pro Leu Ser Leu Ala Leu Gly Thr Val Gly Met Pro Gly Leu Thr 115 120 125 Ala Tyr Phe Gly Leu Leu Glu Ile Cys Gly Val Lys Gly Gly Glu Thr 130 135 140 Val Met Val Asn Ala Ala Ala Gly Ala Val Gly Ser Val Val Gly Gln 145 150 155 160 Ile Ala Lys Leu Lys Gly Cys Lys Val Val Gly Ala Val Gly Ser Asp 165 170 175 Glu Lys Val Ala Tyr Leu Gln Lys Leu Gly Phe Asp Val Val Phe Asn 180 185 190 Tyr Lys Thr Val Glu Ser Leu Glu Glu Thr Leu Lys Lys Ala Ser Pro 195 200 205 Asp Gly Tyr Asp Cys Tyr Phe Asp Asn Val Gly Gly Glu Phe Ser Asn 210 215 220 Thr Val Ile Gly Gln Met Lys Lys Phe Gly Arg Ile Ala Ile Cys Gly 225 230 235 240 Ala Ile Ser Thr Tyr Asn Arg Thr Gly Pro Leu Pro Pro Gly Pro Pro 245 250 255 Pro Glu Ile Val Ile Tyr Gln Glu Leu Arg Met Glu Ala Phe Val Val 260 265 270 Tyr Arg Trp Gln Gly Asp Ala Arg Gln Lys Ala Leu Lys Asp Leu Leu 275 280 285 Lys Trp Val Leu Glu Gly Lys Ile Gln Tyr Lys Glu Tyr Ile Ile Glu 290 295 300 Gly Phe Glu Asn Met Pro Ala Ala Phe Met Gly Met Leu Lys Gly Asp 305 310 315 320 Asn Leu Gly Lys Thr Ile Val Lys Ala 325 <210> 2 <211> 624 <212> PRT <213> Homo sapiens <400> 2 Met Gln Pro Asp Pro Arg Pro Ser Gly Ala Gly Ala Cys Cys Arg Phe 1 5 10 15 Leu Pro Leu Gln Ser Gln Cys Pro Glu Gly Ala Gly Asp Ala Val Met 20 25 30 Tyr Ala Ser Thr Glu Cys Lys Ala Glu Val Thr Pro Ser Gln His Gly 35 40 45 Asn Arg Thr Phe Ser Tyr Thr Leu Glu Asp His Thr Lys Gln Ala Phe 50 55 60 Gly Ile Met Asn Glu Leu Arg Leu Ser Gln Gln Leu Cys Asp Val Thr 65 70 75 80 Leu Gln Val Lys Tyr Gln Asp Ala Pro Ala Ala Gln Phe Met Ala His 85 90 95 Lys Val Val Leu Ala Ser Ser Ser Pro Val Phe Lys Ala Met Phe Thr 100 105 110 Asn Gly Leu Arg Glu Gln Gly Met Glu Val Val Ser Ile Glu Gly Ile 115 120 125 His Pro Lys Val Met Glu Arg Leu Ile Glu Phe Ala Tyr Thr Ala Ser 130 135 140 Ile Ser Met Gly Glu Lys Cys Val Leu His Val Met Asn Gly Ala Val 145 150 155 160 Met Tyr Gln Ile Asp Ser Val Val Arg Ala Cys Ser Asp Phe Leu Val 165 170 175 Gln Gln Leu Asp Pro Ser Asn Ala Ile Gly Ile Ala Asn Phe Ala Glu 180 185 190 Gln Ile Gly Cys Val Glu Leu His Gln Arg Ala Arg Glu Tyr Ile Tyr 195 200 205 Met His Phe Gly Glu Val Ala Lys Gln Glu Glu Phe Phe Asn Leu Ser 210 215 220 His Cys Gln Leu Val Thr Leu Ile Ser Arg Asp Asp Leu Asn Val Arg 225 230 235 240 Cys Glu Ser Glu Val Phe His Ala Cys Ile Asn Trp Val Lys Tyr Asp 245 250 255 Cys Glu Gln Arg Arg Phe Tyr Val Gln Ala Leu Leu Arg Ala Val Arg 260 265 270 Cys His Ser Leu Thr Pro Asn Phe Leu Gln Met Gln Leu Gln Lys Cys 275 280 285 Glu Ile Leu Gln Ser Asp Ser Arg Cys Lys Asp Tyr Leu Val Lys Ile 290 295 300 Phe Glu Glu Leu Thr Leu His Lys Pro Thr Gln Val Met Pro Cys Arg 305 310 315 320 Ala Pro Lys Val Gly Arg Leu Ile Tyr Thr Ala Gly Gly Tyr Phe Arg 325 330 335 Gln Ser Leu Ser Tyr Leu Glu Ala Tyr Asn Pro Ser Asp Gly Thr Trp 340 345 350 Leu Arg Leu Ala Asp Leu Gln Val Pro Arg Ser Gly Leu Ala Gly Cys 355 360 365 Val Val Gly Gly Leu Leu Tyr Ala Val Gly Gly Arg Asn Asn Ser Pro 370 375 380 Asp Gly Asn Thr Asp Ser Ser Ala Leu Asp Cys Tyr Asn Pro Met Thr 385 390 395 400 Asn Gln Trp Ser Pro Cys Ala Pro Met Ser Val Pro Arg Asn Arg Ile 405 410 415 Gly Val Gly Val Ile Asp Gly His Ile Tyr Ala Val Gly Gly Ser His 420 425 430 Gly Cys Ile His His Asn Ser Val Glu Arg Tyr Glu Pro Glu Arg Asp 435 440 445 Glu Trp His Leu Val Ala Pro Met Leu Thr Arg Arg Ile Gly Val Gly 450 455 460 Val Ala Val Leu Asn Arg Leu Leu Tyr Ala Val Gly Gly Phe Asp Gly 465 470 475 480 Thr Asn Arg Leu Asn Ser Ala Glu Cys Tyr Tyr Pro Glu Arg Asn Glu 485 490 495 Trp Arg Met Ile Thr Ala Met Asn Thr Ile Arg Ser Gly Ala Gly Val 500 505 510 Cys Val Leu His Asn Cys Ile Tyr Ala Ala Gly Gly Tyr Asp Gly Gln 515 520 525 Asp Gln Leu Asn Ser Val Glu Arg Tyr Asp Val Glu Thr Glu Thr Trp 530 535 540 Thr Phe Val Ala Pro Met Lys His Arg Arg Ser Ala Leu Gly Ile Thr 545 550 555 560 Val His Gln Gly Arg Ile Tyr Val Leu Gly Gly Tyr Asp Gly His Thr 565 570 575 Phe Leu Asp Ser Val Glu Cys Tyr Asp Pro Asp Thr Asp Thr Trp Ser 580 585 590 Glu Val Thr Arg Met Thr Ser Gly Arg Ser Gly Val Gly Val Ala Val 595 600 605 Thr Met Glu Pro Cys Arg Lys Gln Ile Asp Gln Gln Asn Cys Thr Cys 610 615 620 <210 > 3 <211> 189 <212> PRT <213> Homo sapiens <400> 3 Met Thr Glu Tyr Lys Leu Val Val Val Gly Ala Gly Gly Val Gly Lys 1 5 10 15 Ser Ala Leu Thr Ile Gln Leu Ile Gln Asn His Phe Val Asp Glu Tyr 20 25 30 Asp Pro Thr Ile Glu Asp Ser Tyr Arg Lys Gln Val Val Ile Asp Gly 35 40 45 Glu Thr Cys Leu Leu Asp Ile Leu Asp Thr Ala Gly Gln Glu Glu Tyr 50 55 60 Ser Ala Met Arg Asp Gln Tyr Met Arg Thr Gly Glu Gly Phe Leu Cys 65 70 75 80 Val Phe Ala Ile Asn Asn Thr Lys Ser Phe Glu Asp Ile His His Tyr 85 90 95 Arg Glu Gln Ile Lys Arg Val Lys Asp Ser Glu Asp Val Pro Met Val 100 105 110 Leu Val Gly Asn Lys Cys Asp Leu Pro Ser Arg Thr Val Asp Thr Lys 115 120 125 Gln Ala Gln Asp Leu Ala Arg Ser Tyr Gly Ile Pro Phe Ile Glu Thr 130 135 140 Ser Ala Lys Thr Arg Gln Arg Val Glu Asp Ala Phe Tyr Thr Leu Val 145 150 155 160 Arg Glu Ile Arg Gln Tyr Arg Leu Lys Lys Ile Ser Lys Glu Glu Lys 165 170 175 Thr Pro Gly Cys Val Lys Ile Lys Lys Cys Ile Ile Met 180 185 <210> 4 <211> 393 <212> PRT <213> Homo sapiens <400> 4 Met Glu Glu Pro Gln Ser Asp Pro Ser Val Glu Pro Pro Leu Ser Gln 1 5 10 15 Glu Thr Phe Ser Asp Leu Trp Lys Leu Leu Pro Glu Asn Asn Val Leu 20 25 30 Ser Pro Leu Pro Ser Gln Ala Met Asp Asp Leu Met Leu Ser Pro Asp 35 40 45 Asp Ile Glu Gln Trp Phe Thr Glu Asp Pro Gly Pro Asp Glu Ala Pro 50 55 60 Arg Met Pro Glu Ala Ala Pro Pro Val Ala Pro Ala Pro Ala Ala Pro 65 70 75 80 Thr Pro Ala Ala Pro Ala Pro Ala Pro Ser Trp Pro Leu Ser Ser Ser 85 90 95 Val Pro Ser Gln Lys Thr Tyr Gln Gly Ser Tyr Gly Phe Arg Leu Gly 100 105 110 Phe Leu His Ser Gly Thr Ala Lys Ser Val Thr Cys Thr Tyr Ser Pro 115 120 125 Ala Leu Asn Lys Met Phe Cys Gln Leu Ala Lys Thr Cys Pro Val Gln 130 135 140 Leu Trp Val Asp Ser Thr Pro Pro Pro Pro Gly Thr Arg Val Arg Ala Met 145 150 155 160 Ala Ile Tyr Lys Gln Ser Gln His Met Thr Glu Val Val Arg Arg Cys 165 170 175 Pro His His Glu Arg Cys Ser Asp Ser Asp Gly Leu Ala Pro Pro Gln 180 185 190 His Leu Ile Arg Val Glu Gly Asn Leu Arg Val Glu Tyr Leu Asp Asp 195 200 205 Arg Asn Thr Phe Arg His Ser Val Val Val Pro Tyr Glu Pro Pro Pro Glu 210 215 220 Val Gly Ser Asp Cys Thr Thr Ile His Tyr Asn Tyr Met Cys Asn Ser 225 230 235 240 Ser Cys Met Gly Gly Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr 245 250 255 Leu Glu Asp Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val 260 265 270 Arg Val Cys Ala Cys Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn 275 280 285 Leu Arg Lys Lys Gly Glu Pro His His Glu Leu Pro Pro Gly Ser Thr 290 295 300 Lys Arg Ala Leu Pro Asn Thr Ser Ser Ser Pro Gln Pro Lys Lys 305 310 315 320 Lys Pro Leu Asp Gly Glu Tyr Phe Thr Leu Gln Ile Arg Gly Arg Glu 325 330 335 Arg Phe Glu Met Phe Arg Glu Leu Asn Glu Ala Leu Glu Leu Lys Asp 340 345 350 Ala Gln Ala Gly Lys Glu Pro Gly Gly Ser Arg Ala His Ser Ser His 355 360 365 Leu Lys Ser Lys Lys Gly Gln Ser Thr Ser Arg His Lys Lys Leu Met 370 375 380 Phe Lys Thr Glu Gly Pro Asp Ser Asp 385 390 <210> 5 <211> 433 <212> PRT <213> Homo sapiens <400> 5 Met Glu Val Val Asp Pro Gln Gln Leu Gly Met Phe Thr Glu Gly Glu 1 5 10 15 Leu Met Ser Val Gly Met Asp Thr Phe Ile His Arg Ile Asp Ser Thr 20 25 30 Glu Val Ile Tyr Gln Pro Arg Arg Lys Arg Ala Lys Leu Ile Gly Lys 35 40 45 Tyr Leu Met Gly Asp Leu Leu Gly Glu Gly Ser Tyr Gly Lys Val Lys 50 55 60 Glu Val Leu Asp Ser Glu Thr Leu Cys Arg Arg Ala Val Lys Ile Leu 65 70 75 80 Lys Lys Lys Lys Leu Arg Arg Ile Pro Asn Gly Glu Ala Asn Val Lys 85 90 95 Lys Glu Ile Gln Leu Leu Arg Arg Leu Arg His Lys Asn Val Ile Gln 100 105 110 Leu Val Asp Val Leu Tyr Asn Glu Glu Lys Gln Lys Met Tyr Met Val 115 120 125 Met Glu Tyr Cys Val Cys Gly Met Gln Glu Met Leu Asp Ser Val Pro 130 135 140 Glu Lys Arg Phe Pro Val Cys Gln Ala His Gly Tyr Phe Cys Gln Leu 145 150 155 160 Ile Asp Gly Leu Glu Tyr Leu His Ser Gln Gly Ile Val His Lys Asp 165 170 175 Ile Lys Pro Gly Asn Leu Leu Leu Thr Thr Gly Gly Thr Leu Lys Ile 180 185 190 Ser Asp Leu Gly Val Ala Glu Ala Leu His Pro Phe Ala Ala Asp Asp 195 200 205 Thr Cys Arg Thr Ser Gln Gly Ser Pro Ala Phe Gln Pro Pro Glu Ile 210 215 220 Ala Asn Gly Leu Asp Thr Phe Ser Gly Phe Lys Val Asp Ile Trp Ser 225 230 235 240 Ala Gly Val Thr Leu Tyr Asn Ile Thr Thr Gly Leu Tyr Pro Phe Glu 245 250 255 Gly Asp Asn Ile Tyr Lys Leu Phe Glu Asn Ile Gly Lys Gly Ser Tyr 260 265 270 Ala Ile Pro Gly Asp Cys Gly Pro Pro Leu Ser Asp Leu Leu Lys Gly 275 280 285 Met Leu Glu Tyr Glu Pro Ala Lys Arg Phe Ser Ile Arg Gln Ile Arg 290 295 300 Gln His Ser Trp Phe Arg Lys Lys His Pro Pro Ala Glu Ala Pro Val 305 310 315 320 Pro Ile Pro Pro Ser Pro Asp Thr Lys Asp Arg Trp Arg Ser Met Thr 325 330 335 Val Val Pro Tyr Leu Glu Asp Leu His Gly Ala Asp Glu Asp Glu Asp 340 345 350 Leu Phe Asp Ile Glu Asp Ile Ile Tyr Thr Gln Asp Phe Thr Val 355 360 365 Pro Gly Gln Val Pro Glu Glu Glu Ala Ser His Asn Gly Gln Arg Arg 370 375 380 Gly Leu Pro Lys Ala Val Cys Met Asn Gly Thr Glu Ala Ala Gln Leu 385 390 395 400 Ser Thr Lys Ser Arg Ala Glu Gly Arg Ala Pro Asn Pro Ala Arg Lys 405 410 415 Ala Cys Ser Ala Ser Ser Lys Ile Arg Arg Leu Ser Ala Cys Lys Gln 420 425 430Gln

Claims (9)

1. A method of treating non-small cell lung cancer (NSCLC) in an individual, comprising administering to the individual an effective amount of a composition comprising nanomolar potent particles comprising an acylfulvene, Wherein the treatment is based on an individual suffering from squamous cell carcinoma. The method of claim 1 , wherein the composition comprising nanoparticles comprising paclitaxel and albumin and a platinum-based agent is administered intravenously. The method of claim 1 , wherein the individual is a human. The method of claim 1 , wherein the method further comprises administering radiation. The method of claim 1 , wherein the NSCLC is stage IIIB NSCLC or stage IV NSCLC. The method of claim 1 , wherein the additional therapeutic agent is selected from the group consisting of cisplatin, paclitaxel, and other available treatments. The method of claim 1 , further comprising measuring expression of genetic information in the brain cancer to determine whether expression of genetic information is greater or less than a reference genetic information level. The method of claim 7, wherein the genetic information is PTGR1, KEAP1, KRAS, TP53 or STK11. A method of treating lung cancer in a human subject with targeted drug therapy, comprising:
extracting a biological sample from a human subject;
Measuring the expression level of PTGR1, KEAP1, KRAS, TP53 and STK11 or a combination thereof from the biological sample;
Identifying cancer patients sensitive to illudin-based anticancer drug treatment;
Comprising the step of treating the human subject with an illudin-based anticancer agent having the following structure,

wherein the expression level in the human subject of PTGR1, and one or more of the KEAP1, KRAS, TP53, and STK11 mutations is higher than the level in a human without the solid tumor cancer.