Methods for treating renal cell carcinoma or cancer

Abstract

The method involves treating an individual diagnosed with renal cell carcinoma with a therapeutically effective amount of hydroxyureamethylacylfulvene. The treatment is applicable to various types of renal cell carcinoma, including clear cell renal cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma, and medullary carcinoma.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This international patent application claims the benefit of U.S. Provisional Patent Application No. 63 / 451,159, filed March 9, 2023, which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION This application relates to the treatment of renal cell carcinoma or cancer, and more particularly, this application relates to compositions comprising acylfulvenes and methods of treating kidney cancer using acylfulvenes.

[0003] Renal cancer, also recognized as one of the top 10 most common cancers worldwide, affects approximately 1 in 63 people over the course of their lifetime. Primarily, this type of cancer affects adults aged 50–80 years. A notable trend has been observed, with North America currently reporting the highest incidence of kidney cancer. However, developing countries have seen a consistent and alarming increase in cases over the past 30 years, highlighting the growing global burden of this disease.

[0004] Renal cell carcinoma, alternatively known as kidney cancer or renal cell adenocarcinoma, is characterized by the growth of malignant (cancerous) cells within the lining of the tubules, tiny tubes within the kidneys. Located on each side of the spine and above the lower back, the kidneys function as the body's natural filtration system. They filter blood, removing waste products and converting them into urine. This urine then travels from each kidney through tubes called ureters to the bladder, where it is stored until it leaves the body through the urethra. The most common form of kidney cancer is renal cell carcinoma (RCC), which primarily affects the microscopic tubules within these organs.

[0005] The treatment of renal cell carcinoma (RCC) represents a significant challenge in medicine. It is known as one of the most difficult malignancies to effectively manage due to the limited availability of effective therapies. Currently, biologic therapies offer some, albeit minimal, benefit to patients with RCC. The substantial drug resistance often associated with RCC further complicates treatment. While the exact mechanisms behind this resistance remain unclear, theories suggest a role for altered expression and metabolism of certain membrane transporters. Despite ongoing research, there is a lack of developed anticancer drugs that specifically target RCC, highlighting the urgent need for innovative therapeutic approaches and research in this field.

[0006] Thus, there is a continuing need for improved methods for treating kidney cancer.

[0007] The present application discloses the discovery of treating kidney or renal cancer in a subject with an acylfulvene. In one aspect, the present application provides a method for treating kidney cancer by administering to an affected subject a therapeutically effective amount of an acylfulvene, or a pharmaceutically acceptable salt thereof.

[0008] Another embodiment includes therapy involving the administration of a combination of active agents including illudin or an illudin analogue such as an acylfulvene.

[0009] Another aspect provides a pharmaceutical composition comprising illudin or an illudin analog (e.g., acylfulvene), or a pharmaceutically acceptable salt thereof, in a dose for treating or preventing kidney cancer, mixed with a pharmaceutically suitable carrier or excipient. The pharmaceutical composition can also be administered in combination with other therapeutic agents or modalities, either simultaneously, sequentially, or alternatingly.

[0010] Certain embodiments provide methods for treating subjects, particularly human cancer patients, in need of acylfulvene therapy. This includes patients whose renal cancer has become refractory to standard chemotherapy regimens or whose cancer has recurred after standard chemotherapy. This encompasses renal cancers such as metastatic renal cell carcinoma, Wilms' tumor (nephroblastoma), renal sarcoma, and various benign (non-cancerous) renal tumors such as renal adenoma, neoplastic carcinoma, and angiomyolipoma, with particular emphasis on clear cell renal cell carcinoma.

[0011] Another aspect includes therapies or treatment methods for renal cancer that is either resistant to standard therapies or metastatic, encompassing conditions ranging from clear cell carcinoma of the kidney, metastatic cell carcinoma, Wilms' tumor (nephroblastoma), renal sarcoma, to benign renal tumors including renal adenoma, tumor cell tumors, and angiomyolipoma.

[0012] Another embodiment includes a therapy in which the acylfulvene is (-)-hydroxyureamethyl acylfulvene.

[0013] Another embodiment includes a method for treating kidney cancer in a subject in need thereof, comprising administering to the subject an effective amount of hydroxyureamethylacylfulvene. The hydroxyureamethylacylfulvene can be (-)-hydroxyureamethylacylfulvene, or the hydroxyureamethylacylfulvene is (+)-hydroxyureamethylacylfulvene. The hydroxyureamethylacylfulvene can be administered at a dosage range of 0.1 to 100 mg / kg body weight per day. The kidney cancer can be clear cell renal carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, or collecting duct carcinoma.

[0014] Another aspect includes a pharmaceutical composition for use in treating kidney cancer, comprising hydroxyurea methyl acyl fulvene and a pharmaceutically acceptable carrier. The hydroxyurea methyl acyl fulvene can be administered in combination with at least one other anti-cancer agent.

[0015] Another aspect includes treatments that result in a reduction in tumor size or progression.

[0016] Another aspect of the present application involves the treatment of cancer, which can include solid tumors and hematological malignancies. [Brief explanation of the drawings]

[0017] A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: [Figure 1] The application of LP-184 to various renal cell lines, including both epithelial and carcinoma types, is shown. [Figure 2] It shows that cells containing 6-4 photoproduct (6-4PP) were significantly eradicated after 5 and 7 hours. [Figure 3] Western blot analysis performed on previously investigated cell lines is shown. [Figure 4] 1 shows the sensitivity of various cell lines to LP-184, showing a significant reduction in cell viability over a 72 hour period. DETAILED DESCRIPTION OF THE INVENTION

[0018] The present application provides therapeutic methods for treating renal cell carcinoma or cancer in a subject. One embodiment describes a method for treating a subject with renal cell carcinoma, comprising administering an effective amount of an acylfulvene (e.g., hydroxyureamethyl acylfulvene) or a salt thereof. In other embodiments, the therapy comprises administering a combination of various treatments. One embodiment can specifically involve renal cell carcinoma (RCC). Renal cell carcinoma can include clear cell renal cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, and other rare types of renal cell carcinoma (e.g., collecting duct RCC, multicystic RCC, medullary carcinoma, mucinous tubular and spindle cell carcinoma, neuroblastoma-associated RCC, and unclassified renal cell carcinoma), as well as metastatic RCC. In another embodiment, kidney cancer is defined to include metastatic cell carcinoma, Wilms' tumor (nephroblastoma), renal sarcoma, and benign (non-cancerous) kidney tumors such as renal adenoma, neoplastic carcinoma, and angiomyolipoma.

[0019] Illudin or acylfulvene In one embodiment, the present application contemplates the use of illudin or illudin analogs such as acylfulvenes. Acylfulvenes represent a class of cytotoxic semisynthetic derivatives derived from illudin, a natural compound extracted from the jack-o'-lantern mushroom (Omphalotus olearius). Acylfulvenes are made from the sesquiterpene illudin S by acid treatment (reverse Prince reaction) and exhibit significantly lower reactivity toward thiols compared to illudin S.

[0020] As an example, an acylfulvene that induces a positive shift in light is shown below, specifically (-)-hydroxyureamethyl acylfulvene (called LP-184 by Lantern Pharma Inc.).

[0021] [ka]

[0022] In another example, the acylfulvene used is (+)-hydroxyureamethyl acylfulvene (called LP-284 by Lantern Pharma Inc.), which induces a negative shift in light, as shown below.

[0023] [ka]

[0024] (+)-Hydroxyureamethylacylfulvene and (-)-hydroxyureamethylacylfulvene are enantiomers and are currently known.

[0025] In another example, the acylfulvene under consideration is irofulvene.

[0026] In one embodiment, the patient is treated with radiation before, simultaneously with, and / or after treatment with the acylfulvene.

[0027] In one embodiment, the method comprises administering an acylfulvene to treat kidney cancer. As used herein, the term "renal cancer," as commonly understood in the medical field, refers to cancer originating in the kidney. In some embodiments, the kidney cancer is renal cell carcinoma (RCC). The terms "renal cell carcinoma" and "renal cell carcinoma" refer to cancer originating in the lining of the proximal convoluted tubule. Specifically, RCC includes several common histological subtypes: clear cell renal cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma, and medullary carcinoma, with clear cell renal cell carcinoma (ccRCC) being the most common subtype.

[0028] In another embodiment, a method of treating conventional or clear cell renal cell carcinoma is provided. The cells can be abnormal cells. They can be studied in vitro or in vivo. In certain embodiments, the cells are proliferative cells or stem cells.

[0029] In another embodiment, the second therapeutic agent may consist of one or more chemotherapeutic agents selected from camptothecin derivatives, paclitaxel, docetaxel, epothilone B, 5-FU, gemcitabine, oxaliplatin, cisplatin, carboplatin, melphalan, dacarbazine, temozolomide, doxorubicin, imatinib, erlotinib, bevacizumab, cetuximab, and Raf kinase inhibitors.

[0030] In another embodiment, the second therapeutic agent comprises one or more chemotherapeutic agents selected from paclitaxel and cisplatin.

[0031] Another embodiment includes a pharmaceutical composition comprising a therapeutically effective amount of illudin or an illudin analog, derivative, or pharmaceutically acceptable salt thereof, and a therapeutically effective amount of spironolactone or an analog, derivative, or pharmaceutically acceptable salt thereof. The illudin analog can be hydroxyurea methyl acyl fulvene.

[0032] In another embodiment, a kit for treating cancer in a subject comprises a therapeutically effective amount of illudin or an illudin analog, derivative, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of spironolactone or an analog, derivative, or a pharmaceutically acceptable salt thereof.

[0033] In another embodiment, the second therapeutic agent comprises one or more chemotherapeutic agents selected from camptothecin derivatives, paclitaxel, docetaxel, epothilone B, 5-FU, gemcitabine, oxaliplatin, cisplatin, carboplatin, melphalan, dacarbazine, temozolomide, doxorubicin, imatinib, erlotinib, bevacizumab, cetuximab, and a Raf kinase inhibitor.

[0034] In another embodiment, the second therapeutic agent comprises one or more chemotherapeutic agents selected from paclitaxel or cisplatin.

[0035] In one embodiment, expression or increased expression of the ACTB gene or protein indicates more effective treatment with LP-184 or (-)-hydroxyureamethylacylfulvene. The ACTB gene encodes the β-actin protein, which is part of the actin protein family. This family forms an organized network known as the actin cytoskeleton, which provides structural support within cells. Of the six different types of actin, four are specific to muscle cells and assist in muscle contraction, while the remaining two, β-actin and γ-actin, derived from the ACTG1 gene, are ubiquitous in various cell types throughout the body. In kidney cancer treatments involving ACTB (beta-actin) measurement, the "predetermined level" can be a specific concentration of ACTB in a patient's tissue or blood sample.

[0036] The term "combination therapy" includes the administration of the above-mentioned therapeutic agents in combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation therapy). When combination therapy includes a non-drug treatment, this treatment can be administered at any suitable time, as long as a beneficial effect can be obtained from the combination of the therapeutic agent and the non-drug treatment. For example, a beneficial effect can still be achieved even if the non-drug treatment is separated in time from the administration of the therapeutic agent, potentially by days or even weeks.

[0037] In another aspect, the compositions or combination therapies, or pharmaceutically acceptable salts or solvates thereof, can be administered in combination with radiation therapy, which can be administered as part of a multi-drug therapy, together with a composition of the invention and another chemotherapeutic agent.

[0038] Combination therapy can involve administering two or more drugs, such as acylfulvene, spironolactone, and one or more other therapeutic agents, each of which can be formulated and administered separately, or by administering multiple drugs in a single formulation. Various combinations are possible under combination therapy. For example, two drugs can be combined into one formulation and administered together with a separate formulation containing a third drug. These drugs can be administered simultaneously, or sequentially, with intervals ranging from minutes to weeks apart.

[0039] The therapeutically effective dose may vary depending on the condition being treated, its severity, the route of administration, the age and health of the patient, the use of excipients, potential concomitant therapy, and the judgment of the physician. Effective doses can be guided by the prescribing information for hydroxyurea methyl acyl fulvene or by the relevant medical literature.

[0040] The term "effective amount" refers to an amount of an agent sufficient to alleviate one or more symptoms of a disease or disorder. A "therapeutically effective amount" is an amount sufficient to provide the desired effect in a typical patient. An "effective amount" may delay the onset of symptoms, alter the course of the disease, or reverse the symptoms of the disease. The exact "effective amount" may vary and should be determined by a medical professional through routine experimentation.

[0041] According to the methods described herein, a "subject in need thereof" is a subject diagnosed with kidney cancer, a subject at high risk of kidney cancer compared to the general population, or a subject who does not show a significant response to existing cancer therapies. In this context, "non-responsive" or "refractory" refers to insufficient clinical improvement after treatment. In some scenarios, the subject in need thereof is a cancer patient whose disease is refractory to standard therapy or recurs after standard therapy.

[0042] As described herein, the dosage range for administering a drug depends on factors including the drug's form, potency, and the desired degree of reduction of symptoms, markers, or indicators of a condition, such as the targeted rate of reduction in tumor growth. The dosage should not be so high as to cause adverse side effects. Typically, the dosage varies depending on the patient's age, condition, and sex, and can be determined by one skilled in the art. Furthermore, if complications arise, the dosage can be adjusted by an individual physician.

[0043] The term "therapeutically effective amount" refers to an amount of a pharmaceutical agent sufficient to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. This effect can be assessed by any known assay method. The exact amount required will depend on factors such as the subject's weight, size, and health, the nature and extent of the condition, and the therapy or combination selected. A clinician can determine a therapeutically effective amount through routine experimentation based on their skill and judgment. Preferably, the condition being treated is cancer, but it may also be a cell proliferative disorder.

[0044] The effectiveness of a drug (e.g., for a solid body) in treating a condition described herein or in inducing a described response can be assessed by a skilled clinician. A treatment is considered "effective" if it beneficially alters one or more signs or symptoms of the condition, improves other clinically acceptable symptoms, or induces at least 10% of the desired response according to the described method. Efficacy can be assessed by measuring markers, indicators, symptoms, incidence of the condition being treated, or any other quantifiable parameter, such as tumor size and / or growth rate. Furthermore, efficacy can be assessed by the absence of disease progression, as indicated by the lack of hospitalization or the need for additional medical intervention. Methods for measuring these indicators are well known to those skilled in the art.

[0045] Typical starting doses in clinical trials are 6-12.5 mg / m 2and is generally administered intravenously on a schedule such as once every three or four weeks. In some instances, the effective dose may be the maximum tolerated dose.

[0046] Dosage should be tailored to individual needs. In humans, spironolactone is known to be administered at doses of 25-50 mg daily for heart failure and 100-400 mg daily for hyperaldosteronism. Studies have investigated the use of spironolactone within the 25-400 mg range with respect to potential adverse effects. For cancer treatment, doses can range from 25-400 mg daily. As an example, spironolactone dosage concentrations utilized can range from 5-25 μM (ip) in mice and 20-200 mg daily (oral) in human clinical settings.

[0047] The term "treating" encompasses both therapeutic and prophylactic measures aimed at reducing, suppressing, attenuating, diminishing, halting, or stabilizing the development or progression of a disease, reducing the severity of a disease, or ameliorating symptoms associated with a disease.

[0048] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0049] The compositions of the present invention can form salts, potentially more than one salt per molecule, including one, two, three, etc. All of these forms are contemplated within the scope of the present invention.

[0050] "Pharmaceutically acceptable salts" refers to derivatives of the compounds of the present invention in which the parent compound is modified by making acid or base salts thereof. Examples include mineral or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids, such as, but not limited to, those derived from various acids listed above.

[0051] The term "selectively" typically refers to a preference for occurrence in one population over another, with respect to different cell populations, for example, the compounds of the invention act more frequently or effectively on cancerous cells than on normal cells.

[0052] Routes of administration of the composition or its pharmaceutically acceptable salt or solvate include oral, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, intraperitoneal (IP), subcutaneous, intramuscular, intravenous (IV), rectal, intrapleural, intrathecal, and parenteral. In one embodiment, the compound is administered orally. The preferred route of administration can be determined based on advantages recognized by those skilled in the art.

[0053] Techniques for formulation and administration of the disclosed compounds are well documented and can be found in standard references such as Remington: The Science and Practice of Pharmacy. The compounds, including pharmaceutically acceptable salts, can be used in pharmaceutical preparations, together with suitable carriers or diluents, in dosages adjusted to provide the desired amount of activity within the range discussed.

[0054] Techniques for formulating and administering the compounds disclosed herein are well documented and available in standard references such as "Remington: The Science and Practice of Pharmacy, 19th edition." These compounds, including their pharmaceutically acceptable salts, are suitable for use in pharmaceutical preparations with a suitable carrier or diluent. The composition contains an amount sufficient to provide the desired dose within the range described herein.

[0055] All percentages and ratios used herein are by weight unless otherwise specified. Features and advantages of the present invention will be apparent from the provided examples, which illustrate various components and methodologies. These examples should not be construed as limiting the scope of the invention. Based on this disclosure, one skilled in the art will be able to identify other components and methodologies suitable for practicing the present invention.

[0056] A "subject in need thereof" includes an individual suffering from a precancerous condition or cancer. Subjects include mammals such as humans, primates, dogs, cats, mice, rats, horses, and livestock. Preferably, the subject is a human who has been diagnosed with, is showing symptoms of, or is at risk of developing cancer or a precancerous condition.

[0057] A subject may have a cancer that is refractory or resistant, meaning that the cancer does not respond or stops responding to treatment. This resistance may be inherent at the start of treatment or may develop over time. In some cases, a subject may experience a cancer recurrence after a period of remission or may have exhausted all known effective cancer treatments.

[0058] In some instances, a subject may present with a secondary cancer that arises as a result of a previous cancer treatment, such as chemotherapy or radiation therapy.

[0059] Cancer symptoms vary widely based on the location, size, and effect of the cancer on surrounding organs or tissues. If the cancer has metastasized, symptoms may appear in different parts of the body.

[0060] Successful treatment is often measured by a reduction in tumor size, called “tumor regression.” Ideally, after treatment, the tumor size is reduced by a significant percentage compared to its size before treatment.

[0061] Similarly, successful treatment can result in a reduction in tumor number and size, which can be quantified by a significant percentage reduction compared to the pre-treatment state.

[0062] Effective cancer treatment also results in a reduction in the number of metastatic lesions in tissues or organs distant from the primary tumor site, and can significantly reduce the number of lesions after treatment.

[0063] An increase in the mean survival time of treated subjects compared to subjects receiving standard treatment or a placebo can indicate effective treatment. This increase in survival time preferably exceeds a certain number of days, highlighting the effectiveness of the treatment.

[0064] Furthermore, effectively treating cancer can result in an increase in median survival time compared to subjects who either do not receive treatment or who receive a different monotherapy.

[0065] Successful cancer treatment can also result in a significant reduction in mortality in a population, indicating the effectiveness of the treatment compared to no treatment or a different treatment option.

[0066] Effective treatment of cancer can result in a reduction in the rate of tumor growth. Ideally, the rate of tumor growth is reduced by a significant percentage after treatment, indicating the ability of the treatment to slow or halt tumor progression.

[0067] Furthermore, successful treatment can result in a reduction in tumor regrowth. After an initial treatment phase, the likelihood or extent of tumor recurrence is significantly reduced, further demonstrating the long-term effectiveness of the treatment.

[0068] In the context of treating or preventing a cell proliferative disorder, an affected outcome includes a reduction in the rate of cell proliferation, which after treatment is substantially reduced, indicating a slowing of the proliferation of potentially cancerous or abnormal cells.

[0069] Furthermore, treating or preventing such disorders can result in a reduction in the proportion of proliferating cells, often measured by a mitotic index or similar metric, representing a beneficial shift toward a lower degree of uncontrolled cell division.

[0070] A notable therapeutic effect is also seen in the reduction in size of areas or zones of cellular proliferation: after treatment, these areas, which exhibit aggressive or uncontrolled cellular growth, are significantly reduced, reflecting the effectiveness of the treatment in targeting and limiting cancerous growth.

[0071] Another positive outcome is a reduction in the number or percentage of cells that display an abnormal appearance or morphology. This change, observable under microscopy, indicates normalization of cellular structures potentially affected by cancerous transformation.

[0072] Administration of the compositions of the invention to cells or subjects in need thereof can result in modulation of protein methyltransferase activity, whether stimulating or inhibiting, an effect that selectively targets cancer cells while leaving normal cells largely unaffected.

[0073] Treatment of cancer or cell proliferation disorders can induce cell death, a key component of effective cancer therapy. Preferably, the treatment results in a significant reduction in the number of cells in the treated population, demonstrating the treatment's ability to effectively eradicate cancerous cells. LP-184 is a member of the acylfulvene family of compounds known to induce DNA damage. These damages are typically repaired via the transcription-coupled nucleotide excision repair (TC-NER) pathway.

[0074] Contacting cells with the compositions of the present invention can selectively activate cell death in cancer cells, which is important for effectively combating cancerous growth while minimizing harm to normal cells.

[0075] Methods for treating or preventing cancer involve administering a composition of the invention to produce one or more beneficial outcomes, which may include preventing cancer cell proliferation, inducing cellular senescence, or promoting tumor cell differentiation, all while maintaining a favorable therapeutic index.

[0076] The term "kit" refers to a package that may contain one or more components of a therapeutic regimen, allowing for flexibility in administration. The components can be administered simultaneously or separately, with timing and dosage adjusted to achieve optimal therapeutic outcome.

[0077] The "predetermined level" serves as a threshold that can guide a healthcare provider in deciding whether to initiate, continue, or adjust treatment with an acylfulvene if the patient's ACTB levels are above or below this threshold.

[0078] For detailed descriptions of techniques and methodologies, those skilled in the art can refer to general references, which provide a basis for making or using aspects of the invention and ensure that the practice is based on established scientific knowledge. [Example]

[0079] In order that the disclosure set forth herein may be more efficiently understood, examples are provided below. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the disclosure in any manner.

[0080] Example 1 Figure 1 shows the effects of LP-184 on various renal cell lines, including both epithelial and carcinoma types. The assay assesses the cells' ability to repair 6-4 photoproducts and demonstrates a spectrum of responses. Nonmalignant HK2 cells exhibit typical nonmalignant behavior. 786O and 769P cell lines exhibit low sensitivity. Clear cell renal carcinoma cell lines (e.g., A498 and RXF393) exhibit high sensitivity. Following UV irradiation to induce 6-4 photoproducts (6-4PP), nearly all renal cancer cell lines, along with nonmalignant renal epithelial cell lines, exhibited varying levels of nucleotide excision repair (NER) deficiency, as shown in the figure. In contrast, the RPE1 cell line served as a negative control and showed different responses to treatment.

[0081] Example 2 Figure 2 shows the degree of nucleotide excision repair (NER) deficiency between renal cancer cells and control cells. Cells with 6-4 photoproducts (6-4PP) were significantly eliminated over the 5- and 7-hour periods. 6-4PP is a specific DNA lesion caused by UV radiation associated with adjacent pyrimidine bases (thymine or cytosine) in DNA.

[0082] Such damage, if left unrepaired, can interfere with cellular function, disrupting DNA replication and transcription. This finding indicates that all renal cancer cell lines and renal epithelial non-malignant cell lines had some degree of NER defect that could be targeted by LP-184.

[0083] Example 3 Figure 3 shows Western blot analysis performed on the aforementioned cell lines (non-malignant HK2 cells, which show typical behavior; 786O and 769P lines, which show low sensitivity; and clear cell renal carcinoma cell lines, e.g., A498 and RXF393) examining PTGR1 and ACTB gene expression. The blot shows that cells expressing PTGR1 are more sensitive to LP-184 treatment.

[0084] Example 4 Figure 4 details the sensitivity of various cell lines to LP-184 and shows cell death over a 72-hour period. Sensitivity, as measured by IC50 data, reflects how effectively a substance can inhibit a specific biological or biochemical function. Here, IC50 data reveals the rate at which cells die over a 72-hour period, an important metric for assessing a compound's efficacy. This IC50 value, which indicates the concentration required to reduce cell viability by 50%, is key to understanding the efficacy of a compound and the temporal response of cells to a substance. Such analyses are essential for drug development and therapeutic approaches, providing important insight into how cells respond to different compounds over time.

[0085] Additional IC50 data is shown below. [Table 1]

[0086] Additional IC50 data is shown below. [Table 2]

[0087] Example 5 This example demonstrates the sensitivity of various cell lines to LP-284 and demonstrates cell death over a 72-hour period. Sensitivity, as measured by IC50 data, reflects how effectively a substance can inhibit a specific biological or biochemical function. Here, IC50 data reveals the rate at which cells die over a 72-hour period, an important metric for assessing a compound's efficacy. This IC50 value, which indicates the concentration required to reduce cell viability by 50%, is key to understanding the efficacy of a compound and the temporal response of cells to a substance. Such analyses are essential for drug development and therapeutic approaches, providing important insights into how cells respond to different compounds over time. Such data are presented below.

[0088] [Table 3]

[0089] While several exemplary aspects and embodiments have been provided, those skilled in the art will recognize possible modifications, combinations, permutations, and variations. Accordingly, the appended claims and any claims introduced thereafter should be interpreted to embrace all such modifications, combinations, permutations, and variations within their true spirit and scope.

Claims

1. 1. A method of treating a human having renal cell carcinoma, comprising treating said human with an effective amount of hydroxyureamethylacylfulvene.

2. 2. The method of claim 1, wherein the hydroxyurea methyl acyl fulvene is (-)-hydroxyurea methyl acyl fulvene.

3. 2. The method of claim 1, wherein the hydroxyurea methyl acyl fulvene is (+)-hydroxyurea methyl acyl fulvene.

4. 10. The method of claim 1, wherein the dose is administered intraperitoneally (IP) or intravenously (IV).

5. 1. A method of treating renal cell carcinoma in a patient in need thereof, comprising administering to said patient an acylfulvene or a pharmaceutically acceptable salt thereof.

6. 10. The method of claim 1, wherein the renal cell carcinoma is localized to the kidney.

7. 10. The method of claim 1, wherein the renal cell carcinoma has metastasized.

8. 3. The method of claim 2, wherein the renal cell carcinoma is selected from the group consisting of clear cell renal cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma, and medullary carcinoma.

9. The method of claim 1 , wherein the subject is an animal.

10. The method of claim 1 , wherein the subject is a human.

11. 10. The method of claim 1, further comprising administering at least one additional active agent.

12. 10. The method of claim 1, further comprising administering an additional therapeutic agent selected from the group consisting of cisplatin, paclitaxel, and other available therapies.

13. 1. A method for treating kidney cancer in a subject in need thereof, comprising administering to said subject an effective amount of hydroxyureamethylacylfulvene.

14. 14. The method of claim 13, wherein the hydroxyurea methyl acyl fulvene is (-)-hydroxyurea methyl acyl fulvene.

15. 14. The method of claim 13, wherein the hydroxyurea methyl acyl fulvene is (+)-hydroxyurea methyl acyl fulvene.

16. 14. The method of claim 13, wherein the hydroxyurea methyl acyl fulvene is administered in a dosage range of 0.1 to 100 mg / kg body weight per day.

17. 14. The method of claim 13, wherein the kidney cancer is selected from the group consisting of clear cell renal carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, and collecting duct carcinoma.

18. A pharmaceutical composition comprising hydroxyurea methyl acyl fulvene and a pharmaceutically acceptable carrier for use in treating kidney cancer.

19. 14. The method of claim 13, wherein the hydroxyurea methyl acyl fulvene is administered in combination with at least one other anti-cancer agent.

20. 20. The method of any one of claims 1 to 19, wherein said treatment results in a reduction in tumor size or progression.

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