Diagnostic and therapeutic methods for kras positive cancers

Abstract

Methods are provided for the detection and treatment of cancers having a KRAS mutation, which KRAS mutation may drive tumorigenesis in the cancer. In some embodiments the KRAS+ cancer is a lung adenocarcinoma.

Description

[0001] cross reference

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 472,447, filed March 16, 2017, and U.S. Provisional Patent Application No. 62 / 480,044, filed March 31, 2017, which are hereby incorporated by reference in their entirety .

[0003] Background of the invention

[0004] Treatment of cancer patients has historically included systemic cytotoxic chemotherapy, radiation therapy, and surgery. Improved understanding of the molecular pathways that drive malignancy has now led to the development of agents that target specific molecular pathways in malignant cells, as well as providing an improved ability to identify patients who will benefit from specific therapies. Many established targeted therapies are administered as orally available small molecule kinase inhibitors, but targeted therapies can also be administered intravenously in the form of monoclonal antibodies or small molecules.

[0005] Identification of oncogenic...

Examples

Embodiment 1

[0150] KRAS activates fatty acid synthase leading to specific ERK and lipid signatures associated with lung adenocarcinoma

[0151] Mutations in the KRAS gene cause lung adenocarcinoma. KRAS activation has been associated with altered glucose and glutamine metabolism. Here, KRAS is shown to activate adipogenesis, and this produces distinct proteome and lipid profiles. By gene expression analysis, KRAS was shown to be associated with lipogenic gene signature and specific induction of fatty acid synthase (FASN). Specific changes in lipogenesis and specific lipids were identified by desorption electrospray ionization mass spectrometry imaging (DESI-MSI). By nanoimmunoassay (NIA), KRAS was found to activate the protein ERK2, whereas ERK1 activation was found in non-KRAS-associated human lung tumors. Inhibition of FASN by cerulenin, a small molecule antibiotic, blocked cell proliferation in KRAS-associated lung cancer cells. Thus, KRAS is associated with the activation of ERK2,...

Embodiment 2

[0183] Nanoscale protein measurements can be used to assess intratumor and intrapatient heterogeneity in solid tumors. A nanoimmunoassay (NIA) was used to analyze ERK signaling in fine needle aspiration (FNA) from kidney cancer patients. 39 patients each had 2-3 areas of their kidney tumor sampled by FNA. Such as Figure 15 Indicated in , each circle is tumor FNA averaged across technical replicates (N=91 FNAs). Samples from each patient are connected by vertical lines. Patients are sorted by mean within ERK2 samples. Within isotypes, variation within technical replicates had a mean standard deviation of 1%.

[0184] Among samples from different regions of the same tumor, the variation between samples had a mean standard deviation of 6%. In contrast, standard deviations of proportions measured across different patients ranged from 5% to 22% across isotypes.

[0185] These data suggest that for ERK, a key signaling protein, intra-tumor heterogeneity (6%) is less than intr...

Embodiment 3

[0187] NIA can be used to measure protein in clinical samples from patients with renal cell carcinoma (RCC) and lung cancer

[0188] As described here, NIA charge separation has been used to measure novel proteins in many sample types and in different malignancies. For example, sample types include, but are not limited to, snap frozen tumors, frozen sections embedded in OTC, fine needle aspirate, bone marrow, blood, CTCs, and plasma. Human tumor clinical samples include, but are not limited to, lymphoma, CML, MDS, kidney cancer, lung cancer, and head and neck cancer. Drugs used include, but are not limited to, Atorvastatin, Rigosertide, FTS, and anti-EPHA3. The data presented herein demonstrate that NIA can be used for diagnosis. For kidney cancer, glutaminase levels were measured. For lung cancer, the RAS is distinguished + with RAS - . Furthermore, different types of cancers such as kidney, head and neck cancers are distinguished from each other. The presented data de...

[0001] cross reference

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 472,447, filed March 16, 2017, and U.S. Provisional Patent Application No. 62 / 480,044, filed March 31, 2017, which are hereby incorporated by reference in their entirety .

[0003] Background of the invention

[0004] Treatment of cancer patients has historically included systemic cytotoxic chemotherapy, radiation therapy, and surgery. Improved understanding of the molecular pathways that drive malignancy has now led to the development of agents that target specific molecular pathways in malignant cells, as well as providing an improved ability to identify patients who will benefit from specific therapies. Many established targeted therapies are administered as orally available small molecule kinase inhibitors, but targeted therapies can also be administered intravenously in the form of monoclonal antibodies or small molecules.

[0005] Identification of oncogenic...

Examples

Embodiment 1

[0150] KRAS activates fatty acid synthase leading to specific ERK and lipid signatures associated with lung adenocarcinoma

[0151] Mutations in the KRAS gene cause lung adenocarcinoma. KRAS activation has been associated with altered glucose and glutamine metabolism. Here, KRAS is shown to activate adipogenesis, and this produces distinct proteome and lipid profiles. By gene expression analysis, KRAS was shown to be associated with lipogenic gene signature and specific induction of fatty acid synthase (FASN). Specific changes in lipogenesis and specific lipids were identified by desorption electrospray ionization mass spectrometry imaging (DESI-MSI). By nanoimmunoassay (NIA), KRAS was found to activate the protein ERK2, whereas ERK1 activation was found in non-KRAS-associated human lung tumors. Inhibition of FASN by cerulenin, a small molecule antibiotic, blocked cell proliferation in KRAS-associated lung cancer cells. Thus, KRAS is associated with the activation of ERK2,...

Embodiment 2

[0183] Nanoscale protein measurements can be used to assess intratumor and intrapatient heterogeneity in solid tumors. A nanoimmunoassay (NIA) was used to analyze ERK signaling in fine needle aspiration (FNA) from kidney cancer patients. 39 patients each had 2-3 areas of their kidney tumor sampled by FNA. Such as Figure 15 Indicated in , each circle is tumor FNA averaged across technical replicates (N=91 FNAs). Samples from each patient are connected by vertical lines. Patients are sorted by mean within ERK2 samples. Within isotypes, variation within technical replicates had a mean standard deviation of 1%.

[0184] Among samples from different regions of the same tumor, the variation between samples had a mean standard deviation of 6%. In contrast, standard deviations of proportions measured across different patients ranged from 5% to 22% across isotypes.

[0185] These data suggest that for ERK, a key signaling protein, intra-tumor heterogeneity (6%) is less than intr...

Embodiment 3

[0187] NIA can be used to measure protein in clinical samples from patients with renal cell carcinoma (RCC) and lung cancer

[0188] As described here, NIA charge separation has been used to measure novel proteins in many sample types and in different malignancies. For example, sample types include, but are not limited to, snap frozen tumors, frozen sections embedded in OTC, fine needle aspirate, bone marrow, blood, CTCs, and plasma. Human tumor clinical samples include, but are not limited to, lymphoma, CML, MDS, kidney cancer, lung cancer, and head and neck cancer. Drugs used include, but are not limited to, Atorvastatin, Rigosertide, FTS, and anti-EPHA3. The data presented herein demonstrate that NIA can be used for diagnosis. For kidney cancer, glutaminase levels were measured. For lung cancer, the RAS is distinguished + with RAS - . Furthermore, different types of cancers such as kidney, head and neck cancers are distinguished from each other. The presented data de...

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